Aryl hydrocarbon receptor antagonists and uses thereof

ABSTRACT

The disclosure relates to aryl hydrocarbon receptor antagonists, such as substituted imidazopyridines and imidazopyrazines, as well as methods of expanding hematopoietic stem cells by culturing hematopoietic stem or progenitor cells in the presence of these agents. Additionally, the disclosure provides methods of treating various pathologies in a patient by administration of expanded hematopoietic stem cells. The disclosure further provides methods of synthesizing aryl hydrocarbon receptor antagonists, such as substituted imidazopyridines and imidazopyrazines, as well as kits containing aryl hydrocarbon receptor antagonists that can be used for the expansion of hematopoietic stem cells.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/951,585, filed Apr. 12, 2018, which claims priority to, and thebenefit of, U.S. Application Nos. 62/484,692, filed Apr. 12, 2017,62/613,382, filed Jan. 3, 2018, and 62/625,896, filed Feb. 2, 2018, theentire contents of each of which are incorporated herein by reference.

FIELD

The present disclosure relates to aryl hydrocarbon receptor antagonistsuseful, for example, for ex vivo expansion, enrichment, and maintenanceof hematopoietic stem cells, as well as methods of treating varioushematopoietic pathologies by administration of the expandedhematopoietic stem cells.

BACKGROUND

While hematopoietic stem cells have significant therapeutic potential, alimitation that has hindered their clinical use has been the difficultyassociated with obtaining sufficient numbers of these cells. Inparticular, hematopoietic stem cells are resistant to maintenance,propagation, and expansion ex vivo. Another challenge to be overcome inorder to further develop the use of hematopoietic stem cells (HSCs) as atherapeutic modality is the loss of multi-potency that can occur whenthese cells are cultured ex vivo.

There is currently a need for compositions and methods for the ex vivomaintenance, propagation, and expansion of HSCs that preserve themulti-potency and hematopoietic functionality of such cells.

SUMMARY

The present disclosure features aryl hydrocarbon receptor antagonists,such as substituted imidazopyridines and imidazopyrazines, as well asmethods of expanding hematopoietic stem cells by culturing hematopoieticstem cells in the presence of such agents. Additionally described hereinare methods of chemically synthesizing aryl hydrocarbon receptorantagonists, such as substituted imidazopyridines and imidazopyrazines,as well as kits containing aryl hydrocarbon receptor antagonists thatcan be used for the expansion of hematopoietic stem cells. Additionally,the disclosure provides methods of treating various hematopoieticpathologies in a patient by administration of expanded hematopoieticstem cells. The patient may be suffering, for example, from ahemoglobinopathy or another disease of a cell in the hematopoieticlineage, and is thus in need of hematopoietic stem cell transplantation.As described herein, hematopoietic stem cells are capable ofdifferentiating into a multitude of cell types in the hematopoieticfamily, and can be administered to a patient in order to populate orreconstitute a blood cell type that is deficient in the patient. Thedisclosure thus provides methods of treating a variety of hematopoieticconditions, such as sickle cell anemia, thalassemia, Fanconi anemia,Wiskott-Aldrich syndrome, adenosine deaminase deficiency-severe combinedimmunodeficiency, metachromatic leukodystrophy, Diamond-Blackfan anemiaand Schwachman-Diamond syndrome, human immunodeficiency virus infection,and acquired immune deficiency syndrome, among others.

In a first aspect, the disclosure features a compound represented byformula (I)

wherein L is a linker selected from the group consisting of—NR_(7a)(CR_(8a)R_(8b))_(n)—, —O(CR_(8a)R_(8b))_(n)—,—C(O)(CR_(8a)R_(8b))_(n)—, —C(S)(CR_(8a)R_(8b))_(n)—,—S(O)₀₋₂(CR_(8a)R_(8b))_(n)—, —(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)(CR_(8a)R_(8b))_(n)—, —NR_(7a)C(S)(CR_(8a)R_(8b))_(n)—,—OC(O)(CR_(8a)R_(8b))_(n)—, —OC(S)(CR_(8a)R_(8b))_(n)—,—C(O)NR_(7a)(CR_(8a)R_(8b))_(n)—, —C(S)NR_(7a)(CR_(8a)R_(8b))_(n)—,—C(O)O(CR_(8a)R_(8b))_(n)—, —C(S)O(CR_(8a)R_(8b))_(n)—,—S(O)₂NR_(7a)(CR_(8a)R_(8b))_(n)—, —NR_(7a)S(O)₂(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)NR_(7b)(CR_(8a)R_(8b))_(n)—,—NR_(7a)(CR_(8a)R_(8b))_(n)NR_(7a)—, —NR_(7a)(CR_(8a)R_(8b))_(n)O—,—NR_(7a)(CR_(8a)R_(8b))_(n)S—, —O(CR_(8a)R_(8b))_(n)NR_(7a)—,—O(CR_(8a)R_(8b))_(n)O—, —O(CR_(8a)R_(8b))_(n)S—,—S(CR_(8a)R_(8b))_(n)NR_(7a)—, —S(CR_(8a)R_(8b))_(n)O—,—S(CR_(8a)R_(8b))_(n)S—, and —NR_(7a)C(O)O(CR_(8a)R_(8b))_(n)—, whereinR_(7a), R_(7b), R_(8a), and R_(8b) are each independently selected fromthe group consisting of hydrogen and optionally substituted C1-4 alkyl,and each n is independently an integer from 2 to 6;

R₁ is selected from the group consisting of —S(O)₂NR_(9a)R_(9b),—NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b), —NR_(9a)C(O)NR_(9b)R_(9c),—C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a), —C(O)OR_(9a), —C(S)OR_(9a),—C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b), —NR_(9a)S(O)₂R_(9b),—NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c),—OC(S)CR_(9a)R_(9b)R_(9c), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl, wherein R_(9a), R_(9b), andR_(8c) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl;

R₂ is selected from the group consisting of hydrogen and optionallysubstituted C1-4 alkyl;

R₃ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl;

R₄ is selected from the group consisting of hydrogen and optionallysubstituted C1-4 alkyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

As used herein to describe linkers (represented by “L” in formulas (I),(II), and the like), the notation “-(Linker)-” (wherein “linker” isrepresented using chemical symbols such as NR_(7a)(CR_(8a)R_(8b))_(n),O(CR_(8a)R_(8b))_(n), C(O)(CR_(8a)R_(8b))_(n), C(S)(CR_(8a)R_(8b))_(n),S(O)₀₋₂(CR_(8a)R_(8b))_(n), (CR_(8a)R_(8b))_(n),NR_(7a)C(O)(CR_(8a)R_(8b))_(n), NR_(7a)C(S)(CR_(8a)R_(8b))_(n),OC(O)(CR_(8a)R_(8b))_(n), OC(S)(CR_(8a)R_(8b))_(n),C(O)NR_(7a)(CR_(8a)R_(8b))_(n), C(S)NR_(7a)(CR_(8a)R_(8b))_(n),C(O)O(CR_(8a)R_(8b))_(n), C(S)O(CR_(8a)R_(8b))_(n),S(O)₂NR_(7a)(CR_(8a)R_(8b))_(n), NR_(7a)S(O)₂(CR_(8a)R_(8b))_(n), andNR_(7a)C(O)NR_(7b)(CR_(8a)R_(8b))_(n)) designates that the left hyphenrepresents a covalent bond to the indicated position on theimidazopyridine or imidazopyrazine ring system, while the right hyphenrepresents a covalent bond to R₁.

In some embodiments, R₁ is selected from the group consisting of—S(O)₂NR_(9a)R_(9b), —NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b),—NR_(9a)C(O)NR_(9b)R_(9c), —C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a),—C(O)OR_(9a), —C(S)OR_(9a), —C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b),—NR_(9a)S(O)₂R_(9b), —NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9b),—OC(S)CR_(9a)R_(9b)R_(9c), phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, and 1H-indazolyl, wherein thephenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl, 1H-indolyl,thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl,1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl isoptionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C1-4alkyl, C1-4 alkoxy, halo, halo-substituted-C1-4 alkyl,halo-substituted-C1-4 alkoxy, amino, —O(CH₂)₂NR_(10a)R_(10b),—S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b), and—NR_(10a)S(O)₂R_(10b), wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl.

In some embodiments, R₁ is selected from the group consisting of—S(O)₂NR_(9a)R_(9b), —NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b),—NR_(9a)C(O)NR_(9b)R_(9c), —C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a),—C(O)OR_(9a), —C(S)OR_(9a), —C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b),—NR_(9a)S(O)₂R_(9b), —NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c), and—OC(S)CR_(9a)R_(9b)R_(9c).

In some embodiments, R₁ is selected from the group consisting of phenyl,1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl,pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, and 1H-indazolyl, wherein thephenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl, 1H-indolyl,thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl,1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl isoptionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C1-4alkyl, C₁₋₄ alkoxy, halo, halo-substituted-C1-4 alkyl,halo-substituted-C1-4 alkoxy, amino, —O(CH₂)₂NR_(10a)R_(10b),—S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b), and—NR_(10a)S(O)₂R_(10b).

In some embodiments, R₁ is selected from the group consisting of phenyl,1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl,2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, wherein the phenyl,1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl,2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl is optionally substituted,for example, with from 1 to 3 substituents independently selected fromthe group consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b),and —NR_(10a)S(O)₂R_(10b).

In some embodiments, R₁ is selected from the group consisting of phenyl,phenol-4-yl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl.

In some embodiments, R₁ is selected from the group consisting of:

In some embodiments, R₁ is selected from the group consisting of:

In some embodiments, R₁ is selected from the group consisting ofphenol-4-yl and 1H-indol-3-yl.

In some embodiments, L is selected from the group consisting of—NR_(7a)(CR_(8a)R_(8b))_(n)— and —O(CR_(8a)R_(8b))_(n)—.

In some embodiments, L is selected from the group consisting of—NH(CH₂)₂— and —O(CH₂)₂—.

In some embodiments, R₂ is hydrogen.

In some embodiments, R₃ is selected from the group consisting ofoptionally substituted aryl and optionally substituted heteroaryl.

In some embodiments, R₃ is selected from the group consisting of phenyl,thiophenyl, furanyl, 1H-benzoimidazolyl, quinolinyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl,wherein the phenyl, thiophenyl, furanyl, 1H-benzoimidazolyl, quinolinyl,isoquinolinyl, imidazopyridinyl, benzothiophenyl, pyrimidinyl,pyridinyl, 1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, orthiazolyl is optionally substituted, for example, with from 1 to 3substituents independently selected from the group consisting of cyano,hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and—C(O)NR_(11a)R_(11b), and wherein R_(11a) and R_(11b) are eachindependently selected from the group consisting of hydrogen and C₁₋₄alkyl.

In some embodiments, R₃ is selected from the group consisting ofthiophen-2-yl, thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl,isoquinolin-4-yl, 1H-imidazo[4,5-b]pyridin-1-yl,imidazo[1,2-a]pyridin-3-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-imidazol-1-yl,pyrazin-2-yl, pyridazin-4-yl, 1H-pyrrol-2-yl and thiazol-5-yl, whereinthe thiophen-2-yl, thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl,isoquinolin-4-yl, 1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl,pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,1H-imidazol-1-yl, pyrazin-2-yl, pyridazin-4-yl, 1H-pyrrol-2-yl, orthiazol-5-yl is optionally substituted, for example, with from 1 to 3substituents independently selected from the group consisting of cyano,hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and—C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is selected from the group consisting ofthiophen-3-yl, benzo[b]thiophen-3-yl, pyridin-3-yl, pyrimidin-5-yl,1H-imidazol-1-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, and imidazo[1,2-a]pyridin-3-yl, whereinthe thiophen-3-yl, benzo[b]thiophen-3-yl, pyridin-3-yl, pyrimidin-5-yl,1H-imidazol-1-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, or imidazo[1,2-a]pyridin-3-yl isoptionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C1-4alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is selected from the group consisting ofoptionally substituted:

In some embodiments, R₃ is pyridin-3-yl, wherein the pyridin-3-yl isoptionally substituted at C5, for example, with a substituent selectedfrom the group consisting of C1-4 alkyl, halo, halo-substituted-C1-4alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano,amino, C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and—C(O)NR_(11a)R_(11b).

In some embodiments, the pyridin-3-yl is substituted at C5 with asubstituent selected from the group consisting of ethoxycarbonyl,methoxy, cyano, methyl, methylsulfonyl, fluoro, chloro, trifluoromethyl,ethynyl, and cyclopropyl.

In some embodiments, R₃ is selected from the group consisting of:

In some embodiments, R₃ is imidazo[1,2-a]pyridin-3-yl, wherein theimidazo[1,2-a]pyridin-3-yl is optionally substituted, for example, witha substituent selected from the group consisting of C1-4 alkyl, halo,halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is benzo[b]thiophen-3-yl, wherein thebenzo[b]thiophen-3-yl is optionally substituted, for example, with asubstituent selected from the group consisting of C1-4 alkyl, halo,halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is 1H-imidazo[4,5-b]pyridin-1-yl, wherein the1H-imidazo[4,5-b]pyridin-1-yl is optionally substituted, for example,with a substituent selected from the group consisting of C1-4 alkyl,halo, halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is isoquinolin-4-yl, wherein theisoquinolin-4-yl is optionally substituted, for example, with asubstituent selected from the group consisting of C1-4 alkyl, halo,halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₄ is hydrogen.

In some embodiments, R₅ is selected from the group consisting of C1-10alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of hydroxy, C1-4 alkyl,and halo-substituted-C1-4alkyl.

In some embodiments, R₅ is selected from the group consisting ofisopropyl, methyl, ethyl, prop-1-en-2-yl, isobutyl, cyclohexyl,sec-butyl, (S)-sec-butyl, (R)-sec-butyl, 1-hydroxypropan-2-yl,(S)-1-hydroxypropan-2-yl, (R)-1-hydroxypropan-2-yl, and nonan-2-yl.

In some embodiments, R₅ is (S)-1-hydroxypropan-2-yl.

In some embodiments, R₅ is (R)-1-hydroxypropan-2-yl

In some embodiments, R₅ is (S)-sec-butyl.

In some embodiments, R₅ is (R)-sec-butyl.

In some embodiments, R₅ is selected from the group consisting of (i),(ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl.

In some embodiments, R₅ is selected from the group consisting of:

In some embodiments, R₅ is (ii).

In some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl.

In some embodiments, R₅ is (S)-4-methoxybutan-2-yl.

In some embodiments, R₅ is (R)-4-methoxybutan-2-yl.

In some embodiments, R₅ is (S)-5-methoxypentan-2-yl.

In some embodiments, R₅ is (R)-5-methoxypentan-2-yl.

In some embodiments, R₅ is (S)-4-ethoxybutan-2-yl.

In some embodiments, R₅ is (R)-4-ethoxybutan-2-yl.

In some embodiments, R₆ is hydrogen.

In some embodiments, the disclosure features a compound represented byformula (I-a)

wherein L is a linker selected from the group consisting of—NR_(7a)(CR_(8a)R_(8b))_(n)—, —O(CR_(8a)R_(8b))_(n)—,—C(O)(CR_(8a)R_(8b))_(n)—, —C(S)(CR_(8a)R_(8b))_(n)—,—S(O)₀₋₂(CR_(8a)R_(8b))_(n)—, —(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)(CR_(8a)R_(8b))_(n)—, —NR_(7a)C(S)(CR_(8a)R_(8b))_(n)—,—OC(O)(CR_(8a)R_(8b))_(n)—, —OC(S)(CR_(8a)R_(8b))_(n)—,—C(O)NR_(7a)(CR_(8a)R_(8b))_(n)—, —C(S)NR_(7a)(CR_(8a)R_(8b))_(n)—,—C(O)O(CR_(8a)R_(8b))_(n)—, —C(S)O(CR_(8a)R_(8b))_(n)—,—S(O)₂NR_(7a)(CR_(8a)R_(8b))_(n)—, —NR_(7a)S(O)₂(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)NR_(7b)(CR_(8a)R_(8b))_(n)—, and—NR_(7a)C(O)O(CR_(8a)R_(8b))_(n)—, wherein R_(7a), R_(7b), R_(8a), andR_(8b) are each independently selected from the group consisting ofhydrogen and optionally substituted C1-4 alkyl, and each n isindependently an integer from 2 to 6;

R₁ is selected from the group consisting of —S(O)₂NR_(9a)R_(9b),—NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b), —NR_(9a)C(O)NR_(9b)R_(9c),—C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a), —C(O)OR_(9a), —C(S)OR_(9a),—C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b), —NR_(9a)S(O)₂R_(9b),—NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c),—OC(S)CR_(9a)R_(9b)R_(9c), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl, wherein R_(9a), R_(9b), andR_(9c) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl (for example, R₁ may be selected from thegroup consisting of phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,and 1H-indazolyl, wherein the phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl is optionallysubstituted, for example, with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C1-4 alkyl, C₁₋₄alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b),—OS(O)₂NR_(10a)R_(10b), and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) andR_(10b) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl);

Ar is selected from the group consisting of optionally substitutedmonocyclic aryl and heteroaryl, such as optionally substitutedthiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, Ar is pyridin-3-yl, wherein the pyridin-3-yl isoptionally substituted at C5, for example, with a substituent selectedfrom the group consisting of ethoxycarbonyl, methoxy, cyano, methyl,methylsulfonyl, fluoro, chloro, trifluoromethyl, ethynyl, andcyclopropyl.

In some embodiments, the disclosure features a compound represented byformula (I-b)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,and 1H-indazolyl, wherein the phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl is optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of cyano, hydroxy, C1-4 alkyl, C₁₋₄ alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b),and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

Ar is selected from the group consisting of optionally substitutedmonocyclic aryl and heteroaryl, such as optionally substitutedthiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, A is selected from the group consisting of phenyl,phenol-4-yl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl.

In some embodiments, A is selected from the group consisting ofphenol-4-yl and 1H-indol-3-yl.

In some embodiments, the disclosure features a compound represented byformula (I-c)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,and 1H-indazolyl, wherein the phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl is optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of cyano, hydroxy, C1-4 alkyl, C₁₋₄ alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b),and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

B is an optionally substituted ring system selected from the groupconsisting of thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl,wherein the thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,1H-imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, or thiazolyl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C₁-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, B is pyridin-3-yl, wherein the pyridin-3-yl isoptionally substituted at C5, for example, with a substituent selectedfrom the group consisting of ethoxycarbonyl, methoxy, cyano, methyl,methylsulfonyl, fluoro, chloro, trifluoromethyl, ethynyl, andcyclopropyl.

In some embodiments, the disclosure features a compound represented byformula (I-d)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,and 1H-indazolyl, wherein the phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl is optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of cyano, hydroxy, C1-4 alkyl, C₁₋₄ alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b),and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

B is an optionally substituted ring system selected from the groupconsisting of thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl,wherein the thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,1H-imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, or thiazolyl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C₁-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (I-e)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, whereinthe phenyl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, or 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C1-4 alkyl, C1-4alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b),—OS(O)₂NR_(10a)R_(10b), and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) andR_(10b) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl;

B is an optionally substituted ring system selected from the groupconsisting of thiophen-2-yl, thiophen-3-yl, furan-3-yl,1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, imidazo[1,2-a]pyridin-3-yl,benzo[b]thiophen-3-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1H-imidazol-1-yl, pyrazin-2-yl, pyridazin-4-yl,1H-pyrrol-2-yl and thiazol-5-yl, wherein the thiophen-2-yl,thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-imidazol-1-yl,pyrazin-2-yl, pyridazin-4-yl, 1H-pyrrol-2-yl, or thiazol-5-yl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C₁-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl; or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (I-f)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

each Z is independently a substituent selected from the group consistingof C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a),—S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b), whereinR_(11a) and R_(11b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of isopropyl, methyl, ethyl,prop-1-en-2-yl, isobutyl, cyclohexyl, sec-butyl, (S)-sec-butyl,(R)-sec-butyl, 1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl,(R)-1-hydroxypropan-2-yl, and nonan-2-yl, or R₅ is selected from thegroup consisting of (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, each Z is independently a substituent selected fromthe group consisting of ethoxycarbonyl, methoxy, cyano, methyl,methylsulfonyl, fluoro, chloro, trifluoromethyl, ethynyl, andcyclopropyl.

In some embodiments, the disclosure features a compound represented byformula (I-g)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

Z is a substituent selected from the group consisting of C1-4 alkyl,halo, halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b), wherein R_(11a) and R_(11b) areeach independently selected from the group consisting of hydrogen andC₁₋₄ alkyl; and

R₅ is selected from the group consisting of isopropyl, methyl, ethyl,prop-1-en-2-yl, isobutyl, cyclohexyl, sec-butyl, (S)-sec-butyl,(R)-sec-butyl, 1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl,(R)-1-hydroxypropan-2-yl, and nonan-2-yl, or R₅ is selected from thegroup consisting of (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (I-h)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

r is 0 or 1;

W and V are each independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (I-i)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

r is 0 or 1;

W and V are each independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (I-j)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

r is 0 or 1;

W and V are each independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (I-k)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

r is 0 or 1;

W and V are each independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the compound is compound (1)

or a salt thereof.

In some embodiments, the compound is compound (2)

or a salt thereof.

In some embodiments, the compound is compound (3)

or a salt thereof.

In some embodiments, the compound is compound (4)

or a salt thereof.

In some embodiments, the compound is compound (5)

or a salt thereof.

In some embodiments, the compound is compound (6)

or a salt thereof.

In some embodiments, the compound is compound (7)

or a salt thereof.

In some embodiments, the compound is compound (8)

or a salt thereof.

In some embodiments, the compound is compound (9)

or a salt thereof.

In some embodiments, the compound is compound (10)

or a salt thereof.

In some embodiments, the compound is compound (11)

or a salt thereof.

In some embodiments, the compound is compound (23)

or a salt thereof.

In some embodiments, the compound is compound (25)

or a salt thereof.

In some embodiments, the compound is compound (26)

or a salt thereof.

In another aspect, the disclosure features a compound represented byformula (II)

wherein L is a linker selected from the group consisting of—NR_(7a)(CR_(8a)R_(8b))_(n)—, —O(CR_(8a)R_(8b))_(n)—,—C(O)(CR_(8a)R_(8b))_(n)—, —C(S)(CR_(8a)R_(8b))_(n)—,—S(O)₀₋₂(CR_(8a)R_(8b))_(n)—, —(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)(CR_(8a)R_(8b))_(n)—, —NR_(7a)C(S)(CR_(8a)R_(8b))_(n)—,—OC(O)(CR_(8a)R_(8b))_(n)—, —OC(S)(CR_(8a)R_(8b))_(n)—,—C(O)NR_(7a)(CR_(8a)R_(8b))_(n)—, —C(S)NR_(7a)(CR_(8a)R_(8b))_(n)—,—C(O)O(CR_(8a)R_(8b))_(n)—, —C(S)O(CR_(8a)R_(8b))_(n)—,—S(O)₂NR_(7a)(CR_(8a)R_(8b))_(n)—, —NR_(7a)S(O)₂(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)NR_(7b)(CR_(8a)R_(8b))_(n)—,—NR_(7a)(CR_(8a)R_(8b))_(n)NR_(7a)—, —NR_(7a)(CR_(8a)R_(8b))_(n)O—,—NR_(7a)(CR_(8a)R_(8b))_(n)S—, —O(CR_(8a)R_(8b))_(n)NR_(7a)—,—O(CR_(8a)R_(8b))_(n)O—, —O(CR_(8a)R_(8b))_(n)S—,—S(CR_(8a)R_(8b))_(n)NR_(7a)—, —S(CR_(8a)R_(8b))_(n)O—,—S(CR_(8a)R_(8b))_(n)S—, and —NR_(7a)C(O)O(CR_(8a)R_(8b))_(n)—, whereinR_(7a), R_(7b), R_(8a), and R_(8b) are each independently selected fromthe group consisting of hydrogen and optionally substituted C1-4 alkyl,and each n is independently an integer from 2 to 6;

R₁ is selected from the group consisting of —S(O)₂NR_(9a)R_(9b),—NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b), —NR_(9a)C(O)NR_(9b)R_(9c),—C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a), —C(O)OR_(9a), —C(S)OR_(9a),—C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b), —NR_(9a)S(O)₂R_(9b),—NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c),—OC(S)CR_(9a)R_(9b)R_(9c), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl, wherein R_(9a), R_(9b), andR_(9c) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl;

R₃ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl;

R₄ is selected from the group consisting of hydrogen and optionallysubstituted C1-4 alkyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, R₁ is selected from the group consisting of—S(O)₂NR_(9a)R_(9b), —NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b),—NR_(9a)C(O)NR_(9b)R_(9c), —C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a),—C(O)OR_(9a), —C(S)OR_(9a), —C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b),—NR_(9a)S(O)₂R_(9b), —NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c),—OC(S)CR_(9a)R_(9b)R_(9c), phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, and 1H-indazolyl, wherein thephenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl, 1H-indolyl,thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl,1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl isoptionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C1-4alkyl, C1-4 alkoxy, halo, halo-substituted-C1-4 alkyl,halo-substituted-C1-4 alkoxy, amino, —O(CH₂)₂NR_(10a)R_(10b),—S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b), and—NR_(10a)S(O)₂R_(10b); wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl.

In some embodiments, R₁ is selected from the group consisting of—S(O)₂NR_(9a)R_(9b), —NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b),—NR_(9a)C(O)NR_(9b)R_(9c), —C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a),—C(O)OR_(9a), —C(S)OR_(9a), —C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b),—NR_(9a)S(O)₂R_(9b), —NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c), and—OC(S)CR_(9a)R_(9b)R_(9c).

In some embodiments, R₁ is selected from the group consisting of phenyl,1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl,pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, and 1H-indazolyl, wherein thephenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl, 1H-indolyl,thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl,1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl isoptionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C1-4alkyl, C₁₋₄ alkoxy, halo, halo-substituted-C1-4 alkyl,halo-substituted-C1-4 alkoxy, amino, —O(CH₂)₂NR_(10a)R_(10b),—S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b), and—NR_(10a)S(O)₂R_(10b).

In some embodiments, R₁ is selected from the group consisting of phenyl,1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl,2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, wherein the phenyl,1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl,2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl is optionally substituted,for example, with from 1 to 3 substituents independently selected fromthe group consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b),and —NR_(10a)S(O)₂R_(10b).

In some embodiments, R₁ is selected from the group consisting of phenyl,phenol-4-yl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl.

In some embodiments, R₁ is selected from the group consisting of:

In some embodiments, R₁ is selected from the group consisting of:

In some embodiments, R₁ is selected from the group consisting ofphenol-4-yl and 1H-indol-3-yl.

In some embodiments, L is selected from the group consisting of—NR_(7a)(CR_(8a)R_(8b))_(n)— and —O(CR_(8a)R_(8b))_(n)—.

In some embodiments, L is selected from the group consisting of—NH(CH₂)₂— and —O(CH₂)₂—.

In some embodiments, R₃ is selected from the group consisting ofoptionally substituted aryl and optionally substituted heteroaryl.

In some embodiments, R₃ is selected from the group consisting of phenyl,thiophenyl, furanyl, 1H-benzoimidazolyl, quinolinyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl,wherein the phenyl, thiophenyl, furanyl, 1H-benzoimidazolyl, quinolinyl,isoquinolinyl, imidazopyridinyl, benzothiophenyl, pyrimidinyl,pyridinyl, 1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, orthiazolyl is optionally substituted, for example, with from 1 to 3substituents independently selected from the group consisting of cyano,hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and—C(O)NR_(11a)R_(11b), and wherein R_(11a) and R_(11b) are eachindependently selected from the group consisting of hydrogen and C₁₋₄alkyl.

In some embodiments, R₃ is selected from the group consisting ofthiophen-2-yl, thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl,isoquinolin-4-yl, 1H-imidazo[4,5-b]pyridin-1-yl,imidazo[1,2-a]pyridin-3-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-imidazol-1-yl,pyrazin-2-yl, pyridazin-4-yl, 1H-pyrrol-2-yl and thiazol-5-yl, whereinthe thiophen-2-yl, thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl,isoquinolin-4-yl, 1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl,pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,1H-imidazol-1-yl, pyrazin-2-yl, pyridazin-4-yl, 1H-pyrrol-2-yl, orthiazol-5-yl is optionally substituted, for example, with from 1 to 3substituents independently selected from the group consisting of cyano,hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and—C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is selected from the group consisting ofthiophen-3-yl, benzo[b]thiophen-3-yl, pyridin-3-yl, pyrimidin-5-yl,1H-imidazol-1-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, and imidazo[1,2-a]pyridin-3-yl, whereinthe thiophen-3-yl, benzo[b]thiophen-3-yl, pyridin-3-yl, pyrimidin-5-yl,1H-imidazol-1-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, or imidazo[1,2-a]pyridin-3-yl isoptionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C1-4alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is selected from the group consisting ofoptionally substituted:

In some embodiments, R₃ is pyridin-3-yl, wherein the pyridin-3-yl isoptionally substituted at C5, for example, with a substituent selectedfrom the group consisting of C1-4 alkyl, halo, halo-substituted-C1-4alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano,amino, C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and—C(O)NR_(11a)R_(11b).

In some embodiments, the pyridin-3-yl is substituted at C5 with asubstituent selected from the group consisting of ethoxycarbonyl,methoxy, cyano, methyl, methylsulfonyl, fluoro, chloro, trifluoromethyl,ethynyl, and cyclopropyl.

In some embodiments, R₃ is selected from the group consisting of:

In some embodiments, R₃ is imidazo[1,2-a]pyridin-3-yl, wherein theimidazo[1,2-a]pyridin-3-yl is optionally substituted, for example, witha substituent selected from the group consisting of C1-4 alkyl, halo,halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is benzo[b]thiophen-3-yl, wherein thebenzo[b]thiophen-3-yl is optionally substituted, for example, with asubstituent selected from the group consisting of C1-4 alkyl, halo,halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is 1H-imidazo[4,5-b]pyridin-1-yl, wherein the1H-imidazo[4,5-b]pyridin-1-yl is optionally substituted, for example,with a substituent selected from the group consisting of C1-4 alkyl,halo, halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₃ is isoquinolin-4-yl, wherein theisoquinolin-4-yl is optionally substituted, for example, with asubstituent selected from the group consisting of C1-4 alkyl, halo,halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b).

In some embodiments, R₄ is hydrogen.

In some embodiments, R₅ is selected from the group consisting of C1-10alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of hydroxy, C1-4 alkyl,and halo-substituted-C1-4alkyl.

In some embodiments, R₅ is selected from the group consisting ofisopropyl, methyl, ethyl, prop-1-en-2-yl, isobutyl, cyclohexyl,sec-butyl, (S)-sec-butyl, (R)-sec-butyl, 1-hydroxypropan-2-yl,(S)-1-hydroxypropan-2-yl, (R)-1-hydroxypropan-2-yl, and nonan-2-yl.

In some embodiments, R₅ is (S)-1-hydroxypropan-2-yl.

In some embodiments, R₅ is (R)-1-hydroxypropan-2-yl.

In some embodiments, R₅ is (S)-sec-butyl.

In some embodiments, R₅ is (R)-sec-butyl.

In some embodiments, R₅ is selected from the group consisting of (i),(ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl.

In some embodiments, R₅ is selected from the group consisting of:

In some embodiments, R₅ is (ii).

In some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl.

In some embodiments, R₅ is (S)-4-methoxybutan-2-yl.

In some embodiments, R₅ is (R)-4-methoxybutan-2-yl.

In some embodiments, R₅ is (S)-5-methoxypentan-2-yl.

In some embodiments, R₅ is (R)-5-methoxypentan-2-yl.

In some embodiments, R₅ is (S)-4-ethoxybutan-2-yl.

In some embodiments, R₅ is (R)-4-ethoxybutan-2-yl.

In some embodiments, R₆ is hydrogen.

In some embodiments, the disclosure features a compound represented byformula (II-a)

wherein L is a linker selected from the group consisting of—NR_(7a)(CR_(8a)R_(8b))_(n)—, —O(CR_(8a)R_(8b))_(n)—,—C(O)(CR_(8a)R_(8b))_(n)—, —C(S)(CR_(8a)R_(8b))_(n)—,—S(O)₀₋₂(CR_(8a)R_(8b))_(n)—, —(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)(CR_(8a)R_(8b))_(n)—, —NR_(7a)C(S)(CR_(8a)R_(8b))_(n)—,—OC(O)(CR_(8a)R_(8b))_(n)—, —OC(S)(CR_(8a)R_(8b))_(n)—,—C(O)NR_(7a)(CR_(8a)R_(8b))_(n)—, —C(S)NR_(7a)(CR_(8a)R_(8b))_(n)—,—C(O)O(CR_(8a)R_(8b))_(n)—, —C(S)O(CR_(8a)R_(8b))_(n)—,—S(O)₂NR_(7a)(CR_(8a)R_(8b))_(n)—, —NR_(7a)S(O)₂(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)NR_(7b)(CR_(8a)R_(8b))_(n)—, and—NR_(7a)C(O)O(CR_(8a)R_(8b))_(n)—, wherein R_(7a), R_(7b), R_(8a), andR_(8b) are each independently selected from the group consisting ofhydrogen and optionally substituted C1-4 alkyl, and each n isindependently an integer from 2 to 6;

R₁ is selected from the group consisting of —S(O)₂NR_(9a)R_(9b),—NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b), —NR_(9a)C(O)NR_(9b)R_(9c),—C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a), —C(O)OR_(9a), —C(S)OR_(9a),—C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b), —NR_(9a)S(O)₂R_(9b),—NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c),—OC(S)CR_(9a)R_(9b)R_(9c), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl, wherein R_(9a), R_(9b), andR_(9c) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl (for example, R₁ may be selected from thegroup consisting of phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,and 1H-indazolyl, wherein the phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl is optionallysubstituted, for example, with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C1-4 alkyl, C₁₋₄alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b),—OS(O)₂NR_(10a)R_(10b), and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) andR_(10b) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl);

Ar is selected from the group consisting of optionally substitutedmonocyclic aryl and heteroaryl, such as optionally substitutedthiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, Ar is pyridin-3-yl, wherein the pyridin-3-yl isoptionally substituted at C5, for example, with a substituent selectedfrom the group consisting of ethoxycarbonyl, methoxy, cyano, methyl,methylsulfonyl, fluoro, chloro, trifluoromethyl, ethynyl, andcyclopropyl.

In some embodiments, the disclosure features a compound represented byformula (II-b)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,and 1H-indazolyl, wherein the phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl is optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of cyano, hydroxy, C1-4 alkyl, C₁₋₄ alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b),and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

Ar is selected from the group consisting of optionally substitutedmonocyclic aryl and heteroaryl, such as optionally substitutedthiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, A is selected from the group consisting of phenyl,phenol-4-yl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl.

In some embodiments, A is selected from the group consisting ofphenol-4-yl and 1H-indol-3-yl.

In some embodiments, the disclosure features a compound represented byformula (II-c)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,and 1H-indazolyl, wherein the phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl is optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of cyano, hydroxy, C1-4 alkyl, C₁₋₄ alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b),and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

B is an optionally substituted ring system selected from the groupconsisting of thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl,wherein the thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,1H-imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, or thiazolyl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C₁-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, B is pyridin-3-yl, wherein the pyridin-3-yl isoptionally substituted at C5, for example, with a substituent selectedfrom the group consisting of ethoxycarbonyl, methoxy, cyano, methyl,methylsulfonyl, fluoro, chloro, trifluoromethyl, ethynyl, andcyclopropyl.

In some embodiments, the disclosure features a compound represented byformula (II-d)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,and 1H-indazolyl, wherein the phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl is optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of cyano, hydroxy, C1-4 alkyl, C₁₋₄ alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b),and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

B is an optionally substituted ring system selected from the groupconsisting of thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl,wherein the thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl,1H-imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, or thiazolyl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C₁-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (II-e)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, whereinthe phenyl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, or 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C1-4 alkyl, C1-4alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b),—OS(O)₂NR_(10a)R_(10b), and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) andR_(10b) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl;

B is an optionally substituted ring system selected from the groupconsisting of thiophen-2-yl, thiophen-3-yl, furan-3-yl,1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, imidazo[1,2-a]pyridin-3-yl,benzo[b]thiophen-3-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1H-imidazol-1-yl, pyrazin-2-yl, pyridazin-4-yl,1H-pyrrol-2-yl and thiazol-5-yl, wherein the thiophen-2-yl,thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-imidazol-1-yl,pyrazin-2-yl, pyridazin-4-yl, 1H-pyrrol-2-yl, or thiazol-5-yl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C₁-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C1-4 alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (II-f)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

each Z is independently a substituent selected from the group consistingof C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a),—S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b), whereinR_(11a) and R_(11b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of isopropyl, methyl, ethyl,prop-1-en-2-yl, isobutyl, cyclohexyl, sec-butyl, (S)-sec-butyl,(R)-sec-butyl, 1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl,(R)-1-hydroxypropan-2-yl, and nonan-2-yl, or R₅ is selected from thegroup consisting of (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, each Z is independently a substituent selected fromthe group consisting of ethoxycarbonyl, methoxy, cyano, methyl,methylsulfonyl, fluoro, chloro, trifluoromethyl, ethynyl, andcyclopropyl.

In some embodiments, the disclosure features a compound represented byformula (II-g)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

Z is a substituent selected from the group consisting of C1-4 alkyl,halo, halo-substituted-C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b), wherein R_(11a) and R_(11b) areeach independently selected from the group consisting of hydrogen andC₁₋₄ alkyl; and

R₅ is selected from the group consisting of isopropyl, methyl, ethyl,prop-1-en-2-yl, isobutyl, cyclohexyl, sec-butyl, (S)-sec-butyl,(R)-sec-butyl, 1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl,(R)-1-hydroxypropan-2-yl, and nonan-2-yl, or R₅ is selected from thegroup consisting of (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(11a) and R_(11b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (II-h)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

r is 0 or 1;

W and V are each independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (II-i)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

r is 0 or 1;

W and V are each independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (II-j)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

r is 0 or 1;

W and V are each independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the disclosure features a compound represented byformula (II-k)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl;

q is an integer from 0 to 4;

r is 0 or 1;

W and V are each independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C1-4alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; and

R₅ is selected from the group consisting of C1-10 alkyl, prop-1-en-2-yl,cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl,oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

in some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl;

or a salt thereof.

In some embodiments, the compound is compound (12)

or a salt thereof.

In some embodiments, the compound is compound (13)

or a salt thereof.

In some embodiments, the compound is compound (14)

or a salt thereof.

In some embodiments, the compound is compound (15)

or a salt thereof.

In some embodiments, the compound is compound (16)

or a salt thereof.

In some embodiments, the compound is compound (17)

or a salt thereof.

In some embodiments, the compound is compound (18)

or a salt thereof.

In some embodiments, the compound is compound (19)

or a salt thereof.

In some embodiments, the compound is compound (20)

or a salt thereof.

In some embodiments, the compound is compound (21)

or a salt thereof.

In some embodiments, the compound is compound (22)

or a salt thereof.

In some embodiments, the compound is compound (24)

or a salt thereof.

In some embodiments, the compound is compound (27)

or a salt thereof.

In some embodiments, the compound is compound (28)

or a salt thereof.

In another aspect, the disclosure features a method of producing anexpanded population of hematopoietic stem cells ex vivo, the methodincluding contacting a population of hematopoietic stem cells with thecompound of any one of the above aspects or embodiments in an amountsufficient to produce an expanded population of hematopoietic stemcells.

In another aspect, the disclosure features a method of enriching apopulation of cells with hematopoietic stem cells ex vivo, the methodincluding contacting a population of hematopoietic stem cells with thecompound of any one of the above aspects or embodiments in an amountsufficient to produce a population of cells enriched with hematopoieticstem cells.

In another aspect, the disclosure features a method of maintaining thehematopoietic stem cell functional potential of a population ofhematopoietic stem cells ex vivo for two or more days, the methodincluding contacting a first population of hematopoietic stem cells withthe compound of any one of the above aspects or embodiments, wherein thefirst population of hematopoietic stem cells exhibits a hematopoieticstem cell functional potential after two or more days that is greaterthan that of a control population of hematopoietic stem cells culturedunder the same conditions and for the same time as the first populationof hematopoietic stem cells but not contacted with the compound.

In some embodiments, the first population of hematopoietic stem cellsexhibits a hematopoietic stem cell functional potential after three ormore days (for example, three days, ten days, thirty days, sixty days,or more) of culture that is greater than that of the control populationof hematopoietic stem cells.

In some embodiments, the hematopoietic stem cells are mammalian cells,such as human cells. In some embodiments, the human cells are CD34+cells, such as CD34+ cells are CD34+, CD34+ CD38−, CD34+CD38−CD90+,CD34+CD38−CD90+CD45RA−, CD34+CD38−CD90+CD45RA−CD49F+, orCD34+CD90+CD45RA− cells.

In some embodiments, the hematopoietic stem cells are CD34+hematopoietic stem cells. In some embodiments, the hematopoietic stemcells are CD90+ hematopoietic stem cells. In some embodiments, thehematopoietic stem cells are CD45RA− hematopoietic stem cells. In someembodiments, the hematopoietic stem cells are CD34+CD90+ hematopoieticstem cells. In some embodiments, the hematopoietic stem cells areCD34+CD45RA− hematopoietic stem cells. In some embodiments, thehematopoietic stem cells are CD90+CD45RA− hematopoietic stem cells. Insome embodiments, the hematopoietic stem cells are CD34+CD90+CD45RA−hematopoietic stem cells.

In some embodiments, the hematopoietic stem cells are obtained fromhuman cord blood, mobilized human peripheral blood, or human bonemarrow. The hematopoietic stem cells may, for example, be freshlyisolated from the human or may have been previously cryopreserved.

In some embodiments, the hematopoietic stem cells or progeny thereofmaintain hematopoietic stem cell functional potential after two or moredays upon transplantation of the hematopoietic stem cells into a humansubject.

In some embodiments, the hematopoietic stem cells or progeny thereof arecapable of localizing to hematopoietic tissue and reestablishinghematopoiesis upon transplantation of the hematopoietic stem cells intoa human subject.

In some embodiments, upon transplantation into a human subject, thehematopoietic stem cells give rise to a population of cells selectedfrom the group consisting of megakaryocytes, thrombocytes, platelets,erythrocytes, mast cells, myoblasts, basophils, neutrophils,eosinophils, microglia, granulocytes, monocytes, osteoclasts,antigen-presenting cells, macrophages, dendritic cells, natural killercells, T-lymphocytes, and B-lymphocytes.

In another aspect, the disclosure features a method of treating apatient (e.g., a human patient) suffering from a stem cell disorder, themethod including administering to the patient a population ofhematopoietic stem cells, wherein the hematopoietic stem cells wereproduced by contacting the hematopoietic stem cells or progenitorsthereof with a compound of any of the above aspects or embodiments.

In another aspect, the disclosure features a method of preparing anexpanded population of hematopoietic stem cells for transplantation intoa patient (e.g., a human patient) suffering from a stem cell disorder,the method including contacting a first population of hematopoietic stemcells with a compound of any of the above aspects or embodiments for atime sufficient to produce the expanded population of hematopoietic stemcells.

In another aspect, the disclosure features a method of treating apatient (e.g., a human patient) suffering from a stem cell disorder, themethod including:

-   -   a. preparing an expanded population of hematopoietic stem cells        by contacting a first population of hematopoietic stem cells        with a compound of any of the above aspects or embodiments; and    -   b. administering the expanded population of hematopoietic stem        cells to the patient.

In yet another aspect, provided herein is a method of treating a stemcell disorder in a patient (e.g., a human patient) in need thereof,comprising administering an expanded population of hematopoietic stemcells to the patient, wherein the expanded population of hematopoieticstem cells is prepared by contacting a first population of hematopoieticstem cells with a compound of any of the above aspects or embodimentsfor a time sufficient to produce the expanded population ofhematopoietic stem cells.

In some embodiments, the stem cell disorder is a hemoglobinopathy.

In some embodiments, the stem cell disorder is selected from the groupconsisting of sickle cell anemia, thalassemia, Fanconi anemia, andWiskott-Aldrich syndrome.

In some embodiments, the stem cell disorder is Fanconi anemia.

In some embodiments, the stem cell disorder is a myelodysplasticdisorder.

In some embodiments, the stem cell disorder is an immunodeficiencydisorder, such as a congenital immunodeficiency or an acquiredimmunodeficiency. The acquired immunodeficiency may be, for example,human immunodeficiency virus (HIV) or acquired immune deficiencysyndrome (AIDS).

In some embodiments, the stem cell disorder is a metabolic disorder,such as a glycogen storage disease, a mucopolysaccharidose, Gaucher'sDisease, Hurlers Disease, a sphingolipidose, or metachromaticleukodystrophy.

In some embodiments, the stem cell disorder is cancer, such as ahematological cancer. The cancer may be, for example, leukemia,lymphoma, multiple myeloma, or neuroblastoma. In some embodiments, thecancer is acute myeloid leukemia, acute lymphoid leukemia, chronicmyeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuselarge B-cell lymphoma, or non-Hodgkin's lymphoma.

In some embodiments, the stem cell disorder is a disorder selected fromthe group consisting of adenosine deaminase deficiency and severecombined immunodeficiency, hyper immunoglobulin M syndrome,Chediak-Higashi disease, hereditary lymphohistiocytosis, osteopetrosis,osteogenesis imperfecta, storage diseases, thalassemia major, systemicsclerosis, systemic lupus erythematosus, multiple sclerosis, andjuvenile rheumatoid arthritis.

In some embodiments, the stem cell disorder is an autoimmune disorder.For example, the stem cell disorder may be multiple sclerosis, humansystemic lupus, rheumatoid arthritis, inflammatory bowel disease,treating psoriasis, Type 1 diabetes mellitus, acute disseminatedencephalomyelitis, Addison's disease, alopecia universalis, ankylosingspondylitisis, antiphospholipid antibody syndrome, aplastic anemia,autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner eardisease, autoimmune lymphoproliferative syndrome, autoimmune oophoritis,Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy,Chagas' disease, chronic fatigue immune dysfunction syndrome, chronicinflammatory demyelinating polyneuropathy, Crohn's disease, cicatricalpemphigoid, coeliac sprue-dermatitis herpetiformis, cold agglutinindisease, CREST syndrome, Degos disease, discoid lupus, dysautonomia,endometriosis, essential mixed cryoglobulinemia,fibromyalgia-fibromyositis, Goodpasture's syndrome, Grave's disease,Guillain-Barre syndrome, Hashimoto's thyroiditis, Hidradenitissuppurativa, idiopathic and/or acute thrombocytopenic purpura,idiopathic pulmonary fibrosis, IgA neuropathy, interstitial cystitis,juvenile arthritis, Kawasaki's disease, lichen planus, Lyme disease,Meniere disease, mixed connective tissue disease, myasthenia gravis,neuromyotonia, opsoclonus myoclonus syndrome, optic neuritis, Ord'sthyroiditis, pemphigus vulgaris, pernicious anemia, polychondritis,polymyositis and dermatomyositis, primary biliary cirrhosis,polyarteritis nodosa, polyglandular syndromes, polymyalgia rheumatica,primary agammaglobulinemia, Raynaud phenomenon, Reiter's syndrome,rheumatic fever, sarcoidosis, scleroderma, Sjögren's syndrome, stiffperson syndrome, Takayasu's arteritis, temporal arteritis, ulcerativecolitis, uveitis, vasculitis, vitiligo, vulvodynia, or Wegener'sgranulomatosis.

In some embodiments, the stem cell disorder is a neurological disorder,such as Parkinson's disease, Alzheimer's disease, multiple sclerosis,Amyotrophic lateral sclerosis, Huntington's disease, mild cognitiveimpairment, amyloidosis, AIDS-related dementia, encephalitis, stroke,head trauma, epilepsy, mood disorders, or dementia.

In another aspect, provided herein is a method of producing microglia inthe central nervous system of a patient (e.g., a human patient) in needthereof, comprising administering an expanded population ofhematopoietic stem cells to the patient, wherein the expanded populationof hematopoietic stem cells is prepared by contacting a first populationof hematopoietic stem cells with a compound of any of the above aspectsor embodiments for a time sufficient to produce the expanded populationof hematopoietic stem cells, and wherein administration of the expandedpopulation of hematopoietic stem cells results in formation of microgliain the central nervous system of the patient.

In another aspect, the disclosure features a composition comprising apopulation of hematopoietic stem cells, wherein the hematopoietic stemcells or progenitors thereof have been contacted with the compound ofany one of the above aspects or embodiments, thereby expanding thehematopoietic stem cells or progenitors thereof.

In another aspect, the disclosure features a kit including the compoundof any one of the above aspects or embodiments and a package insert,wherein the package insert instructs a user of the kit to contact apopulation of hematopoietic stem cells with the compound for a timesufficient to produce an expanded population of hematopoietic stemcells.

In another aspect, the disclosure features a kit including the compoundof any one of the above aspects or embodiments and a package insert,wherein the package insert instructs a user of the kit to contact apopulation of cells including hematopoietic stem cells with the compoundfor a time sufficient to produce a population of cells enriched withhematopoietic stem cells.

In another aspect, the disclosure features a kit including the compoundof any one of the above aspects or embodiments and a package insert,wherein the package insert instructs a user of the kit to contact apopulation of hematopoietic stem cells with the compound for a timesufficient to maintain the hematopoietic stem cell functional potentialof the population of hematopoietic stem cells ex vivo for two or moredays.

In some embodiments, the kit further includes a population of cellsincluding hematopoietic stem cells.

In another aspect, the disclosure features a compound of any of theabove aspects or embodiments for use in producing an expanded populationof hematopoietic stem cells ex vivo.

In another aspect, the disclosure features a compound of any of theabove aspects or embodiments for use in enriching a population of cellswith hematopoietic stem cells ex vivo.

In another aspect, the disclosure features a compound of any of theabove aspects or embodiments for use in maintaining the hematopoieticstem cell functional potential of a population of hematopoietic stemcells ex vivo for two or more days.

In another aspect, the disclosure features use of a compound of any ofthe above aspects or embodiments in producing an expanded population ofhematopoietic stem cells ex vivo.

In another aspect, the disclosure features use of a compound of any ofthe above aspects or embodiments in enriching a population of cells withhematopoietic stem cells ex vivo.

In another aspect, the disclosure features use of a compound of any ofthe above aspects or embodiments in maintaining the hematopoietic stemcell functional potential of a population of hematopoietic stem cells exvivor for two or more days.

In another aspect, the disclosure features a composition for use intreating a human patient suffering from a disorder, said compositioncomprising a population of hematopoietic stem cells, wherein saidhematopoietic stem cells were produced by contacting said hematopoieticstem cells or progenitors thereof with a compound of any of the aboveaspects or embodiments.

In another aspect, the disclosure features a composition for use intreating a human patient suffering from a disorder, said compositioncomprising an expanded population of hematopoietic stem cells preparedby contacting a first population of hematopoietic stem cells with acompound of any of the above aspects or embodiments for a timesufficient to produce said expanded population of hematopoietic stemcells.

In another aspect, the disclosure features use of a compound of any ofthe above aspects or embodiments in preparing a medicament for treatinga human patient suffering from a disorder.

In some embodiments, the disorder is selected from hemoglobinopathy,sickle cell anemia, thalassemia, Fanconi anemia, Wiskott-Aldrichsyndrome, a myelodysplastic disorder, an immunodeficiency disorder, ametabolic disorder, cancer, adenosine deaminase deficiency and severecombined immunodeficiency, hyper immunoglobulin M syndrome,Chediak-Higashi disease, hereditary lymphohistiocytosis, osteopetrosis,osteogenesis imperfecta, storage diseases, thalassemia major, systemicsclerosis, systemic lupus erythematosus, multiple sclerosis, juvenilerheumatoid arthritis, an autoimmune disorder, and a neurologicaldisorder.

In some embodiments, the immunodeficiency disorder is a congenitalimmunodeficiency.

In some embodiments, the immunodeficiency disorder is an acquiredimmunodeficiency.

In some embodiments, the acquired immunodeficiency is humanimmunodeficiency virus or acquired immune deficiency syndrome.

In some embodiments, the metabolic disorder is selected from the groupconsisting of glycogen storage diseases, mucopolysaccharidoses, GauchersDisease, Hurlers Disease, sphingolipidoses, and metachromaticleukodystrophy.

In some embodiments, the cancer is a hematological cancer.

In some embodiments, the cancer is selected from the group consisting ofleukemia, lymphoma, multiple myeloma, and neuroblastoma.

In some embodiments, the cancer is acute myeloid leukemia, acutelymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia,multiple myeloma, diffuse large B-cell lymphoma, or non-Hodgkin'slymphoma.

In some embodiments, the autoimmune disorder is selected from the groupconsisting of multiple sclerosis, human systemic lupus, rheumatoidarthritis, inflammatory bowel disease, treating psoriasis, Type 1diabetes mellitus, acute disseminated encephalomyelitis, Addison'sdisease, alopecia universalis, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease,autoimmune lymphoproliferative syndrome, autoimmune oophoritis, Balodisease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Chagas'disease, chronic fatigue immune dysfunction syndrome, chronicinflammatory demyelinating polyneuropathy, Crohn's disease, cicatricalpemphigoid, coeliac sprue-dermatitis herpetiformis, cold agglutinindisease, CREST syndrome, Degos disease, discoid lupus, dysautonomia,endometriosis, essential mixed cryoglobulinemia,fibromyalgia-fibromyositis, Goodpasture's syndrome, Grave's disease,Guillain-Barre syndrome, Hashimoto's thyroiditis, Hidradenitissuppurativa, idiopathic and/or acute thrombocytopenic purpura,idiopathic pulmonary fibrosis, IgA neuropathy, interstitial cystitis,juvenile arthritis, Kawasaki's disease, lichen planus, Lyme disease,Meniere disease, mixed connective tissue disease, myasthenia gravis,neuromyotonia, opsoclonus myoclonus syndrome, optic neuritis, Ord'sthyroiditis, pemphigus vulgaris, pernicious anemia, polychondritis,polymyositis and dermatomyositis, primary biliary cirrhosis,polyarteritis nodosa, polyglandular syndromes, polymyalgia rheumatica,primary agammaglobulinemia, Raynaud phenomenon, Reiter s syndrome,rheumatic fever, sarcoidosis, scleroderma, Sjögren's syndrome, stiffperson syndrome, Takayasu's arteritis, temporal arteritis, ulcerativecolitis, uveitis, vasculitis, vitiligo, vulvodynia, and Wegener'sgranulomatosis.

In some embodiments, the neurological disorder is selected from thegroup consisting of Parkinson's disease, Alzheimer's disease, multiplesclerosis, Amyotrophic lateral sclerosis, Huntington's disease, mildcognitive impairment, amyloidosis, AIDS-related dementia, encephalitis,stroke, head trauma, epilepsy, mood disorders, and dementia.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods and examples areillustrative only and are not intended to be limiting. In the case ofconflict between the chemical structures and names of the compoundsdisclosed herein, the chemical structures will control.

Other features and advantages of the disclosure will be apparent fromthe following detailed description and claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph demonstrating the effect of compound (5) and compound(16) on the aryl hydrocarbon receptor-driven expression of luciferase inthe absence of the aryl hydrocarbon receptor agonist VAF347 intransiently transfected HepG2 cells in vitro. Experimental details forthis experiment are reported in Example 3, below.

FIG. 2 is a graph demonstrating the effect of compound (5) and compound(16) on the aryl hydrocarbon receptor-driven expression of luciferase inthe presence of the aryl hydrocarbon receptor agonist VAF347 intransiently transfected HepG2 cells in vitro. Experimental details forthis experiment are reported in Example 3, below.

FIG. 3 is a graph demonstrating the effect of compound (5) and compound(16) on the quantity of CD34+ cells in a hematopoietic stem cellpopulation over the course of a seven-day experiment. Experimentaldetails for this experiment are reported in Example 3, below.

FIG. 4 is a scheme showing the design of experiments, described inExample 5, below, aimed at examining the ability of hematopoietic stemcells to migrate to central nervous system tissue and promote theengraftment of microglial cells in the brain.

FIGS. 5A and 5B are graphs showing the ability of hematopoietic stemcells expanded, ex vivo, in the presence of compound (16) to increasethe frequency of CD45+ cells in peripheral blood of NSG mice, and topromote the engraftment of microglial cells in the brains of NSG mice.Each bar graph shows the median value obtained upon examination of n=8NSG mice.

FIGS. 6A and 6B are graphs showing the ability of hematopoietic stemcells expanded, ex vivo, in the presence of compound (24) to increasethe frequency of CD45+ cells in peripheral blood of NSG mice, and topromote the engraftment of microglial cells in the brains of NSG mice.Each bar graph shows the median value obtained upon examination of n=6-8NSG mice.

FIG. 7 sets forth a ¹H-NMR spectra of compound (24) in DMSO-d6.

FIG. 8 sets forth a ¹H-NMR spectra of an isolated compound (24)enantiomer peak in DMSO-d6.

FIG. 9 sets forth a ¹H-NMR spectra of an isolated compound (24)enantiomer peak in DMSO-d6.

FIG. 10 sets forth a ¹H-NMR spectra of compound (27) in chloroform-d.

FIG. 11 sets forth a ¹H-NMR spectra of compound (28) in chloroform-d.

FIG. 12 is a graph demonstrating expansion capabilities of AHRantagonists in terms of CD34+ frequency. Experimental details for thisexperiment are reported in Example 9, below.

FIG. 13 is a graph demonstrating expansion capabilities of AHRantagonists in terms of CD34+ number. Experimental details for thisexperiment are reported in Example 9, below.

FIG. 14 is a graph demonstrating endogeneous AHR antagonist activity.Experimental details for this experiment are reported in Example 9,below.

FIG. 15 is a graph demonstrating AHR antagonist activity in the presenceof VAF347. Experimental details for this experiment are reported inExample 9, below.

DETAILED DESCRIPTION

The compositions and methods described herein provide tools forexpanding hematopoietic stem cells, for instance, by culturinghematopoietic stem cells ex vivo in the presence of an aryl hydrocarbonreceptor antagonist represented by formula (I) or (II) described herein.It has presently been discovered that aryl hydrocarbon receptorantagonists of the formula (I) or (II) described herein are capable ofinducing the proliferation of hematopoietic stem cells while maintainingthe hematopoietic stem cell functional potential of the ensuing cells.As hematopoietic stem cells exhibit the ability to differentiate into amultitude of cell types within the hematopoietic lineage, the arylhydrocarbon receptor antagonists described herein can be used to amplifya population of hematopoietic stem cells prior to transplantation of thehematopoietic stem cells to a patient in need thereof. Exemplarypatients in need of a hematopoietic stem cell transplant are thosesuffering from a hemoglobinopathy, immunodeficiency, or metabolicdisease, such as one of the various pathologies described herein.

Despite the promise of hematopoietic stem cell transplant therapy,methods of expanding hematopoietic stem cells ex vivo to producequantities sufficient for transplantation has been challenging due tothe propensity of hematopoietic stem cells to differentiate uponproliferation. The aryl hydrocarbon receptor antagonists describedherein represent a solution to this long-standing difficulty, as thecompounds set forth herein are capable of inducing the expansion ofhematopoietic stem cells while preserving their capacity forreconstituting various populations of cells in the hematopoietic family.The compositions described herein therefore provide useful tools for theproliferation of hematopoietic stem cells prior to hematopoietic stemcell transplant therapy, and thus constitute methods of treating avariety of hematopoietic conditions, such as sickle cell anemia,thalassemia, Fanconi anemia, Wiskott-Aldrich syndrome, adenosinedeaminase deficiency-severe combined immunodeficiency, metachromaticleukodystrophy, Diamond-Blackfan anemia and Schwachman-Diamond syndrome,human immunodeficiency virus infection, and acquired immune deficiencysyndrome, among others.

Definitions

Listed below are definitions of various terms used in this application.These definitions apply to terms as they are used throughout thisspecification and claims, unless otherwise limited in specificinstances, either individually or as part of a larger group.

As used herein, the term “about” refers to a value that is within 10%above or below the value being described. For example, the term “about 5nM” indicates a range of from 4.5 nM to 5.5 nM.

As used herein, the term “donor” refers to a human or animal from whichone or more cells are isolated prior to administration of the cells, orprogeny thereof, into a recipient. The one or more cells may be, forexample, a population of hematopoietic stem cells.

As used herein, the term “endogenous” describes a substance, such as amolecule, cell, tissue, or organ (for example, a hematopoietic stem cellor a cell of hematopoietic lineage, such as a megakaryocyte,thrombocyte, platelet, erythrocyte, mast cell, myoblast, basophil,neutrophil, eosinophil, microglial cell, granulocyte, monocyte,osteoclast, antigen-presenting cell, macrophage, dendritic cell, naturalkiller cell, T-lymphocyte, or B-lymphocyte) that is found naturally in aparticular organism, such as a human patient.

As used herein, the term “engraftment potential” is used to refer to theability of hematopoietic stem and progenitor cells to repopulate atissue, whether such cells are naturally circulating or are provided bytransplantation. The term encompasses all events surrounding or leadingup to engraftment, such as tissue homing of cells and colonization ofcells within the tissue of interest. The engraftment efficiency or rateof engraftment can be evaluated or quantified using any clinicallyacceptable parameter as known to those of skill in the art and caninclude, for example, assessment of competitive repopulating units(CRU); incorporation or expression of a marker in tissue(s) into whichstem cells have homed, colonized, or become engrafted; or by evaluationof the progress of a subject through disease progression, survival ofhematopoietic stem and progenitor cells, or survival of a recipient.Engraftment can also be determined by measuring white blood cell countsin peripheral blood during a post-transplant period. Engraftment canalso be assessed by measuring recovery of marrow cells by donor cells ina bone marrow aspirate sample.

As used herein, the term “exogenous” describes a substance, such as amolecule, cell, tissue, or organ (for example, a hematopoietic stem cellor a cell of hematopoietic lineage, such as a megakaryocyte,thrombocyte, platelet, erythrocyte, mast cell, myoblast, basophil,neutrophil, eosinophil, microglial cell, granulocyte, monocyte,osteoclast, antigen-presenting cell, macrophage, dendritic cell, naturalkiller cell, T-lymphocyte, or B-lymphocyte) that is not found naturallyin a particular organism, such as a human patient. Exogenous substancesinclude those that are provided from an external source to an organismor to cultured matter extracted therefrom.

As used herein, the term “expanding amount” refers to a quantity orconcentration of an agent, such as an aryl hydrocarbon receptorantagonist described herein, sufficient to induce the proliferation of apopulation of CD34+ cells (e.g., a CD34+ CD90+ cells), for example, byfrom about 1.1-fold to about 1,000-fold, or more (e.g., about 1.1-fold,1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold,1.9-fold, 2-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold,2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3-fold, 3.1-fold, 3.2-fold,3.3-fold, 3.4-fold, 3.5-fold, 3.6-fold, 3.7-fold, 3.8-fold, 3.9-fold,4-fold, 4.1-fold, 4.2-fold, 4.3-fold, 4.4-fold, 4.5-fold, 4.6-fold,4.7-fold, 4.8-fold, 4.9-fold, 5-fold, 5.1-fold, 5.2-fold, 5.3-fold,5.4-fold, 5.5-fold, 5.6-fold, 5.7-fold, 5.8-fold, 5.9-fold, 6-fold,6.1-fold, 6.2-fold, 6.3-fold, 6.4-fold, 6.5-fold, 6.6-fold, 6.7-fold,6.8-fold, 6.9-fold, 7-fold, 7.1-fold, 7.2-fold, 7.3-fold, 7.4-fold,7.5-fold, 7.6-fold, 7.7-fold, 7.8-fold, 7.9-fold, 8-fold, 8.1-fold,8.2-fold, 8.3-fold, 8.4-fold, 8.5-fold, 8.6-fold, 8.7-fold, 8.8-fold,8.9-fold, 9-fold, 9.1-fold, 9.2-fold, 9.3-fold, 9.4-fold, 9.5-fold,9.6-fold, 9.7-fold, 9.8-fold, 9.9-fold, 10-fold, 50-fold, 100-fold,200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold,900-fold, 1,000-fold, or more).

As used herein, the term “hematopoietic stem cells” (“HSCs”) refers toimmature blood cells having the capacity to self-renew and todifferentiate into mature blood cells comprising diverse lineagesincluding but not limited to granulocytes (e.g., promyelocytes,neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes,erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producingmegakaryocytes, platelets), monocytes (e.g., monocytes, macrophages),dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NKcells, B-cells and T-cells). Such cells may include CD34+ cells. CD34+cells are immature cells that express the CD34 cell surface marker. Inhumans, CD34+ cells are believed to include a subpopulation of cellswith the stem cell properties defined above, whereas in mice, HSCs areCD34−. In addition, HSCs also refer to long term repopulating HSCs(LT-HSC) and short term repopulating HSCs (ST-HSC). LT-HSCs and ST-HSCsare differentiated, based on functional potential and on cell surfacemarker expression. For example, human HSCs are CD34+, CD38−, CD45RA−,CD90+, CD49F+, and lin− (negative for mature lineage markers includingCD2, CD3, CD4, CD7, CD8, CD10, CD11B, CD19, CD20, CD56, CD235A). Inmice, bone marrow LT-HSCs are CD34−, SCA-1+, C-kit+, CD135−,Slamfl/CD150+, CD48−, and lin− (negative for mature lineage markersincluding Ter119, CD11 b, Gr1, CD3, CD4, CD8, B220, IL7ra), whereasST-HSCs are CD34+, SCA-1+, C-kit+, CD135−, Slamfl/CD150+, and lin—(negative for mature lineage markers including Ter119, CD11b, Gr1, CD3,CD4, CD8, B220, IL7ra). In addition, ST-HSCs are less quiescent and moreproliferative than LT-HSCs under homeostatic conditions. However, LT-HSChave greater self renewal potential (i.e., they survive throughoutadulthood, and can be serially transplanted through successiverecipients), whereas ST-HSCs have limited self renewal (i.e., theysurvive for only a limited period of time, and do not possess serialtransplantation potential). Any of these HSCs can be used in the methodsdescribed herein. ST-HSCs are particularly useful because they arehighly proliferative and thus, can more quickly give rise todifferentiated progeny.

As used herein, the term “hematopoietic progenitor cells” includespluripotent cells capable of differentiating into several cell types ofthe hematopoietic system, including, without limitation, granulocytes,monocytes, erythrocytes, megakaryocytes, B-cells and T-cells, amongothers. Hematopoietic progenitor cells are committed to thehematopoietic cell lineage and generally do not self-renew.Hematopoietic progenitor cells can be identified, for example, byexpression patterns of cell surface antigens, and include cells havingthe following immunophenotype: CD34+ or CD34+CD90−. Hematopoieticprogenitor cells include short-term hematopoietic stem cells,multi-potent progenitor cells, common myeloid progenitor cells,granulocyte-monocyte progenitor cells, and megakaryocyte-erythrocyteprogenitor cells. The presence of hematopoietic progenitor cells can bedetermined functionally, for instance, by detecting colony-forming unitcells, e.g., in complete methylcellulose assays, or phenotypicallythrough the detection of cell surface markers using flow cytometry andcell sorting assays described herein and known in the art.

As used herein, the term “hematopoietic stem cell functional potential”refers to the functional properties of hematopoietic stem cells whichinclude 1) multi-potency (which refers to the ability to differentiateinto multiple different blood lineages including, but not limited to,granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils),erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g.,megakaryoblasts, platelet producing megakaryocytes, platelets),monocytes (e.g., monocytes, macrophages), dendritic cells, microglia,osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells), 2)self-renewal (which refers to the ability of hematopoietic stem cells togive rise to daughter cells that have equivalent potential as the mothercell, and further that this ability can repeatedly occur throughout thelifetime of an individual without exhaustion), and 3) the ability ofhematopoietic stem cells or progeny thereof to be reintroduced into atransplant recipient whereupon they home to the hematopoietic stem cellniche and re-establish productive and sustained hematopoiesis.

As used herein, patients that are “in need of” a hematopoietic stem celltransplant include patients that exhibit a defect or deficiency in oneor more blood cell types, as well as patients having a stem celldisorder. Hematopoietic stem cells generally exhibit 1) multi-potency,and can thus differentiate into multiple different blood lineagesincluding, but not limited to, granulocytes (e.g., promyelocytes,neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes,erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producingmegakaryocytes, platelets), monocytes (e.g., monocytes, macrophages),dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NKcells, B-cells and T-cells), 2) self-renewal, and can thus give rise todaughter cells that have equivalent potential as the mother cell, and 3)the ability to be reintroduced into a transplant recipient whereuponthey home to the hematopoietic stem cell niche and re-establishproductive and sustained hematopoiesis. Hematopoietic stem cells canthus be administered to a patient defective or deficient in one or morecell types of the hematopoietic lineage in order to re-constitute thedefective or deficient population of cells in vivo. For example, thepatient may be suffering from cancer, and the deficiency may be causedby administration of a chemotherapeutic agent or other medicament thatdepletes, either selectively or non-specifically, the cancerous cellpopulation. Additionally or alternatively, the patient may be sufferingfrom a non-malignant hemoglobinopathy, such as sickle cell anemia,thalassemia, Fanconi anemia, and Wiskott-Aldrich syndrome. The subjectmay be one that is suffering from adenosine deaminase severe combinedimmunodeficiency (ADA SCID), HIV/AIDS, metachromatic leukodystrophy,Diamond-Blackfan anemia, and Schwachman-Diamond syndrome. The subjectmay have or be affected by an inherited blood disorder (e.g., sicklecell anemia) or an autoimmune disorder. Additionally or alternatively,the subject may have or be affected by a malignancy, such as amalignancy selected from the group consisting of hematologic cancers(e.g., leukemia, lymphoma, multiple myeloma, or myelodysplasticsyndrome) and neuroblastoma. In some embodiments, the subject has or isotherwise affected by a metabolic disorder. For example, the subject maysuffer or otherwise be affected by a metabolic disorder selected fromthe group consisting of glycogen storage diseases,mucopolysaccharidoses, Gaucher's Disease, Hurlers Disease,sphingolipidoses, metachromatic leukodystrophy, or any other diseases ordisorders which may benefit from the treatments and therapies disclosedherein and including, without limitation, severe combinedimmunodeficiency, Wiscott-Aldrich syndrome, hyper immunoglobulin M (IgM)syndrome, Chediak-Higashi disease, hereditary lymphohistiocytosis,osteopetrosis, osteogenesis imperfecta, storage diseases, thalassemiamajor, sickle cell disease, systemic sclerosis, systemic lupuserythematosus, multiple sclerosis, juvenile rheumatoid arthritis andthose diseases, or disorders described in “Bone Marrow Transplantationfor Non-Malignant Disease,” ASH Education Book, 1:319-338 (2000), thedisclosure of which is incorporated herein by reference in its entiretyas it pertains to pathologies that may be treated by administration ofhematopoietic stem cell transplant therapy. Additionally oralternatively, a patient “in need of” a hematopoietic stem celltransplant may one that is or is not suffering from one of the foregoingpathologies, but nonetheless exhibits a reduced level (e.g., as comparedto that of an otherwise healthy subject) of one or more endogenous celltypes within the hematopoietic lineage, such as megakaryocytes,thrombocytes, platelets, erythrocytes, mast cells, myoblasts, basophils,neutrophils, eosinophils, microglia, granulocytes, monocytes,osteoclasts, antigen-presenting cells, macrophages, dendritic cells,natural killer cells, T-lymphocytes, and B-lymphocytes. One of skill inthe art can readily determine whether one's level of one or more of theforegoing cell types, or other blood cell type, is reduced with respectto an otherwise healthy subject, for instance, by way of flow cytometryand fluorescence activated cell sorting (FACS) methods, among otherprocedures, known in the art.

As used herein, the term “recipient” refers to a patient that receives atransplant, such as a transplant containing a population ofhematopoietic stem cells. The transplanted cells administered to arecipient may be, e.g., autologous, syngeneic, or allogeneic cells.

As used herein, the term “sample” refers to a specimen (e.g., blood,blood component (e.g., serum or plasma), urine, saliva, amniotic fluid,cerebrospinal fluid, tissue (e.g., placental or dermal), pancreaticfluid, chorionic villus sample, and cells) taken from a subject.

As used herein, the terms “subject” and “patient” refer to an organism,such as a human, that receives treatment for a particular disease orcondition as described herein. For instance, a patient, such as a humanpatient, that is in need of hematopoietic stem cell transplantation mayreceive treatment that includes a population of hematopoietic stem cellsso as to treat a stem cell disorder, such as a cancer, autoimmunedisease, or metabolic disorder described herein. For instance, apatient, such as a human patient suffering from a stem cell disorder,may receive treatment in the form of a population of hematopoietic stemcells, such as a population of from about 1×10⁶ to about 1×10⁹hematopoietic stem cells.

As used herein, the phrase “stem cell disorder” broadly refers to anydisease, disorder, or condition that may be treated or cured byengrafting or transplanting a population of hematopoietic stem orprogenitor cells in a target tissue within a patient. For example, TypeI diabetes has been shown to be cured by hematopoietic stem celltransplant, along with various other disorders. Diseases that can betreated by infusion of hematopoietic stem or progenitor cells into apatient include, sickle cell anemia, thalassemias, Fanconi anemia,aplastic anemia, Wiskott-Aldrich syndrome, ADA SCID, HIV/AIDS,metachromatic leukodystrophy, Diamond-Blackfan anemia, andSchwachman-Diamond syndrome. Additional diseases that may be treated bytransplantation of hematopoietic stem and progenitor cells as describedherein include blood disorders (e.g., sickle cell anemia) and autoimmunedisorders, such as scleroderma, multiple sclerosis, ulcerative colitis,and Chrohn's disease. Additional diseases that may be treated usinghematopoietic stem and progenitor cell transplant therapy includecancer, such as a cancer described herein. Stem cell disorders include amalignancy, such as a neuroblastoma or a hematologic cancers, such asleukemia, lymphoma, and myeloma. For instance, the cancer may be acutemyeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia,chronic lymphoid leukemia, multiple myeloma, diffuse large B-celllymphoma, or non-Hodgkin's lymphoma. Disorders that may be treated bytransplanting a population of hematopoietic stem cells to a patientinclude neurological disorders, such as Parkinson's disease, Alzheimer'sdisease, multiple sclerosis, Amyotrophic lateral sclerosis, Huntington'sdisease, mild cognitive impairment, amyloidosis, AIDS-related dementia,encephalitis, stroke, head trauma, epilepsy, mood disorders, anddementia. As described herein, without being limited by mechanism, theability of hematopoietic stem cell transplantation to treat suchdisorders may be due, in part, to the capacity of hematopoietic stemcells to migrate to the central nervous system and differentiate intomicroglial cells, thereby repopulating a hematopoietic cell line thatmay be damaged or deficient in patients having a neurological disorder.Additional diseases treatable using hematopoietic stem or progenitorcell transplant therapy include myelodysplastic syndrome. In someembodiments, the patient has or is otherwise affected by a metabolicstorage disorder. For example, the patient may suffer or otherwise beaffected by a metabolic disorder selected from the group consisting ofglycogen storage diseases, mucopolysaccharidoses, Gaucher's Disease,Hurlers Disease, sphingolipidoses, metachromatic leukodystrophy, or anyother diseases or disorders which may benefit from the treatments andtherapies disclosed herein and including, without limitation, severecombined immunodeficiency, Wiscott-Aldrich syndrome, hyperimmunoglobulin M (IgM) syndrome, Chediak-Higashi disease, hereditarylymphohistiocytosis, osteopetrosis, osteogenesis imperfecta, storagediseases, thalassemia major, sickle cell disease, systemic sclerosis,systemic lupus erythematosus, multiple sclerosis, juvenile rheumatoidarthritis and those diseases, or disorders described in “Bone MarrowTransplantation for Non-Malignant Disease,” ASH Education Book,1:319-338 (2000), the disclosure of which is incorporated herein byreference in its entirety as it pertains to pathologies that may betreated by administration of hematopoietic stem or progenitor celltransplant therapy.

As used herein, the terms “treat”, “treating” or “treatment” refer to amethod of alleviating or abating a disease and/or its attendantsymptoms. As used herein, the terms “preventing” or “prevent” describesreducing or eliminating the onset of the symptoms or complications ofthe disease, condition, or disorder. As used herein, the terms“disease(s)”, “disorder(s)”, and “condition(s)” are usedinterchangeably, unless the context clearly dictates otherwise.

“Treating” may refer to therapeutic treatment, in which the object is toprevent or slow down (lessen) an undesired physiological change ordisorder or to promote a beneficial phenotype in the patient beingtreated. Beneficial or desired clinical results include, but are notlimited to, the observation of an increase in the cell count or relativeconcentration of hematopoietic stem cells in a patient in need of ahematopoietic stem cell transplant following administration of anexogenous hematopoietic stem cell graft to the patient. Beneficialresults of therapy described herein may also include an increase in thecell count or relative concentration of one or more cells ofhematopoietic lineage, such as a megakaryocyte, thrombocyte, platelet,erythrocyte, mast cell, myoblast, basophil, neutrophil, eosinophil,microglial cell, granulocyte, monocyte, osteoclast, antigen-presentingcell, macrophage, dendritic cell, natural killer cell, T-lymphocyte, orB-lymphocyte, following conditioning therapy and subsequenthematopoietic stem cell transplant therapy. Additional beneficialresults may include the reduction in quantity of a disease-causing cellpopulation, such as a population of cancer cells or auto-immune cells.

As used herein, the terms “variant” and “derivative” are usedinterchangeably and refer to naturally-occurring, synthetic, andsemi-synthetic analogues of a compound, peptide, protein, or othersubstance described herein. A variant or derivative of a compound,peptide, protein, or other substance described herein may retain orimprove upon the biological activity of the original material.

As used herein, the term “alkyl” refers to a straight- or branched-chainalkyl group having, for example, from 1 to 20 carbon atoms in the chain,or, in certain embodiments, from 1 to 6 carbon atoms in the chain.Examples of alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, tert-pentyl, neopentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and the like.

As used herein, the term “alkylene” refers to a straight- orbranched-chain divalent alkyl group. The divalent positions may be onthe same or different atoms within the alkyl chain. Examples of alkyleneinclude methylene, ethylene, propylene, isopropylene, and the like.

As used herein, the term “heteroalkyl” refers to a straight orbranched-chain alkyl group having, for example, from 1 to 20 carbonatoms in the chain, and further containing one or more heteroatoms(e.g., oxygen, nitrogen, or sulfur, among others) in the chain.

As used herein, the term “heteroalkylene” refers to a straight- orbranched-chain divalent heteroalkyl group. The divalent positions may beon the same or different atoms within the heteroalkyl chain. Thedivalent positions may be one or more heteroatoms.

As used herein, the term “alkenyl” refers to a straight- orbranched-chain alkenyl group having, for example, from 2 to 20 carbonatoms in the chain. It denotes a monovalent group derived from ahydrocarbon moiety containing, for example, from two to six carbon atomshaving at least one carbon-carbon double bond. The double bond may ormay not be the point of attachment to another group. Examples of alkenylgroups include, but are not limited to, vinyl, propenyl, isopropenyl,butenyl, tert-butylenyl, 1-methyl-2-buten-1-yl, hexenyl, and the like.

As used herein, the term “alkenylene” refers to a straight- orbranched-chain divalent alkenyl group. The divalent positions may be onthe same or different atoms within the alkenyl chain. Examples ofalkenylene include ethenylene, propenylene, isopropenylene, butenylene,and the like.

As used herein, the term “heteroalkenyl” refers to a straight- orbranched-chain alkenyl group having, for example, from 2 to 20 carbonatoms in the chain, and further containing one or more heteroatoms(e.g., oxygen, nitrogen, or sulfur, among others) in the chain.

As used herein, the term “heteroalkenylene” refers to a straight- orbranched-chain divalent heteroalkenyl group. The divalent positions maybe on the same or different atoms within the heteroalkenyl chain. Thedivalent positions may be one or more heteroatoms.

As used herein, the term “alkynyl” refers to a straight- orbranched-chain alkynyl group having, for example, from 2 to 20 carbonatoms in the chain and at least one carbon-carbon triple bond. Examplesof alkynyl groups include, but are not limited to, propargyl, butynyl,pentynyl, hexynyl, and the like.

As used herein, the term “alkynylene” refers to a straight- orbranched-chain divalent alkynyl group. The divalent positions may be onthe same or different atoms within the alkynyl chain.

As used herein, the term “heteroalkynyl” refers to a straight- orbranched-chain alkynyl group having, for example, from 2 to 20 carbonatoms in the chain, and further containing one or more heteroatoms(e.g., oxygen, nitrogen, or sulfur, among others) in the chain.

As used herein, the term “heteroalkynylene” refers to a straight- orbranched-chain divalent heteroalkynyl group. The divalent positions maybe on the same or different atoms within the heteroalkynyl chain. Thedivalent positions may be one or more heteroatoms.

As used herein, the term “cycloalkyl” refers to a monocyclic, or fused,bridged, or spiro polycyclic ring structure that is saturated and has,for example, from 3 to 12 carbon ring atoms. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[3.1.0]hexane, and the like. Alsocontemplated is a monovalent group derived from a monocyclic orpolycyclic carbocyclic ring compound having at least one carbon-carbondouble bond by the removal of at least one or two hydrogen atoms.Examples of such groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl,

As used herein, the term “cycloalkylene” refers to a divalent cycloalkylgroup. The divalent positions may be on the same or different atomswithin the ring structure. Examples of cycloalkylene includecyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and thelike.

As used herein, the term “heterocyloalkyl” or “heterocyclyl” refers to amonocyclic, or fused, bridged, or spiro polycyclic ring structure thatis saturated and has, for example, from 3 to 12 ring atoms per ringstructure selected from carbon atoms and heteroatoms selected from,e.g., nitrogen, oxygen, and sulfur, among others. The ring structure maycontain, for example, one or more oxo groups on carbon, nitrogen, orsulfur ring members. Exemplary heterocycloalkyl groups include, but arenot limited to, [1,3] dioxolane, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, piperazinyl, piperidinyl,oxazolidinyl, isooxazolidinyl, morpholinyl, thiazololidinyl,isothiazolidinyl, and tetrahydrofuryl.

As used herein, the term “heterocycloalkylene” refers to a divalentheterocyclolalkyl group. The divalent positions may be on the same ordifferent atoms within the ring structure.

As used herein, the term “aryl” refers to a monocyclic or multicyclicaromatic ring system containing, for example, from 6 to 19 carbon atoms.Aryl groups include, but are not limited to, phenyl, fluorenyl,naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Thedivalent positions may be one or more heteroatoms.

As used herein, the term “arylene” refers to a divalent aryl group. Thedivalent positions may be on the same or different atoms.

As used herein, the term “heteroaryl” refers to a monocyclicheteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromaticgroup. In certain embodiments, the heteroaryl group contains five to tenring atoms of which one ring atom is selected from S, O, and N; zero,one, or two ring atoms are additional heteroatoms independently selectedfrom S, O, and N; and the remaining ring atoms are carbon. Heteroarylgroups include, but are not limited to, pyridyl, pyrrolyl, furyl,thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl,isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl,isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl,benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl,quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl,pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl,tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl,purinyl, pteridinyl, carbazolyl, xanthenyl, benzoquinolyl, and the like.

As used herein, the term “heteroarylene” refers to a divalent heteroarylgroup. The divalent positions may be on the same or different atoms. Thedivalent positions may be one or more heteroatoms.

Unless otherwise constrained by the definition of the individualsubstituent, the foregoing chemical moieties, such as “alkyl”,“alkylene”, “heteroalkyl”, “heteroalkylene”, “alkenyl”, “alkenylene”,“heteroalkenyl”, “heteroalkenylene”, “alkynyl”, “alkynylene”,“heteroalkynyl”, “heteroalkynylene”, “cycloalkyl”, “cycloalkylene”,“heterocyclolalkyl”, heterocycloalkylene”, “aryl,” “arylene”,“heteroaryl”, and “heteroarylene” groups can optionally be substituted.As used herein, the term “optionally substituted” refers to a compoundor moiety containing one or more (for example, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, or more) substituents, as permitted by the valence of thecompound or moiety or a site thereof, such as a substituent selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, alkyl aryl, alkyl heteroaryl, alkyl cycloalkyl, alkylheterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino,aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl,sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl,cyano, hydroxy, mercapto, nitro, and the like. The substitution mayinclude situations in which neighboring substituents have undergone ringclosure, such as ring closure of vicinal functional substituents, toform, for instance, lactams, lactones, cyclic anhydrides, acetals,hemiacetals, thioacetals, aminals, and hemiaminals, formed by ringclosure, for example, to furnish a protecting group.

As used herein, the term “optionally substituted” refers to a chemicalmoiety that may have one or more chemical substituents, as valencypermits, such as C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-10cycloalkyl, C2-10 heterocyclolalkyl, C2-10 aryl, C2-10 alkylaryl, C2-10heteroaryl, C2-10 alkylheteroaryl, amino, ammonium, acyl, acyloxy,acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, sulfinyl,sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano,hydroxy, mercapto, nitro, and the like. An optionally substitutedchemical moiety may contain, e.g., neighboring substituents that haveundergone ring closure, such as ring closure of vicinal functionalsubstituents, thus forming, e.g., lactams, lactones, cyclic anhydrides,acetals, thioacetals, or aminals formed by ring closure, for instance,in order to generate protecting group.

In accordance with the application, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group.

The terms “hal,” “halo,” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

As described herein, compounds of the application and moieties presentin the compounds may optionally be substituted with one or moresubstituents, such as are illustrated generally above, or as exemplifiedby particular classes, subclasses, and species of the application. Itwill be appreciated that the phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted.” Ingeneral, the term “substituted”, whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Unlessotherwise indicated, an optionally substituted group may have asubstituent at each substitutable position of the group, and when morethan one position in any given structure may be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at every position. The terms“optionally substituted”, “optionally substituted alkyl,” “optionallysubstituted alkenyl,” “optionally substituted alkynyl”, “optionallysubstituted cycloalkyl,” “optionally substituted cycloalkenyl,”“optionally substituted aryl”, “optionally substituted heteroaryl,”“optionally substituted aralkyl”, “optionally substitutedheteroaralkyl,” “optionally substituted heterocycloalkyl,” and any otheroptionally substituted group as used herein, refer to groups that aresubstituted or unsubstituted by independent replacement of one, two, orthree or more of the hydrogen atoms thereon with substituents including,but not limited to:

—F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C3-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONN—C₃-C₁₂-cycloalkyl, —CONN-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, —NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NHheterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NHheterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

Compounds of Formula (I) and Formula (II)

The aryl hydrocarbon receptor antagonists described herein includecompounds represented by formula (I) or formula (II):

wherein L is a linker selected from the group consisting of—NR_(7a)(CR_(8a)R_(8b))_(n)—, —O(CR_(8a)R_(8b))_(n)—,—C(O)(CR_(8a)R_(8b))_(n)—, —C(S)(CR_(8a)R_(8b))_(n)—,—S(O)₀₋₂(CR_(8a)R_(8b))_(n)—, —(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)(CR_(8a)R_(8b))_(n)—, —NR_(7a)C(S)(CR_(8a)R_(8b))_(n)—,—OC(O)(CR_(8a)R_(8b))_(n)—, —OC(S)(CR_(8a)R_(8b))_(n)—,—C(O)NR_(7a)(CR_(8a)R_(8b))_(n)—, —C(S)NR_(7a)(CR_(8a)R_(8b))_(n)—,—C(O)O(CR_(8a)R_(8b))_(n)—, —C(S)O(CR_(8a)R_(8b))_(n)—,—S(O)₂NR_(7a)(CR_(8a)R_(8b))_(n)—, —NR_(7a)S(O)₂(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)NR_(7b)(CR_(8a)R_(8b))_(n)—, and—NR_(7a)C(O)O(CR_(8a)R_(8b))_(n)—, wherein R_(7a), R_(7b), R_(8a), andR_(8b) are each independently selected from the group consisting ofhydrogen and optionally substituted C1-4 alkyl, and each n isindependently an integer from 2 to 6;

R₁ is selected from the group consisting of —S(O)₂NR_(9a)R_(9b),—NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b), —NR_(9a)C(O)NR_(9b)R_(9c),—C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a), —C(O)OR_(9a), —C(S)OR_(9a),—C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b), —NR_(9a)S(O)₂R_(9b),—NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9b),—OC(S)CR_(9a)R_(9b)R_(9b), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl, wherein R_(9a), R_(9b), andR_(9b) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl;

R₂ is selected from the group consisting of hydrogen and optionallysubstituted C1-4 alkyl;

R₃ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl;

R₄ is selected from the group consisting of hydrogen and optionallysubstituted C1-4 alkyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl;

or a salt thereof.

In some embodiments, R₁ is selected from the group consisting of—S(O)₂NR_(9a)R_(9b), —NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b),—NR_(9a)C(O)NR_(9b)R_(9c), —C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a),—C(O)OR_(9a), —C(S)OR_(9a), —C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b),—NR_(9a)S(O)₂R_(9b), —NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9b),—OC(S)CR_(9a)R_(9b)R_(9c), phenyl, 1H-pyrrolopyridinyl,1H-pyrrolopyridinyl, 1H-indolyl, thiophenyl, pyridinyl,1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl,2-oxo-2,3-dihydro-1H-benzoimidazolyl, and 1H-indazolyl, wherein thephenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl, 1H-indolyl,thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl,1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl, or 1H-indazolyl isoptionally substituted, for example, with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C1-4alkyl, C1-4 alkoxy, halo, halo-substituted-C1-4 alkyl,halo-substituted-C1-4 alkoxy, amino, —O(CH₂)₂NR_(10a)R_(10b),—S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b), and—NR_(10a)S(O)₂R_(10b), wherein R_(10a) and R_(10b) are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl. Forinstance, R₁ may be selected from the group consisting of—S(O)₂NR_(9a)R_(9b), —NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b),—NR_(9a)C(O)NR_(9b)R_(9c), —C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a),—C(O)OR_(9a), —C(S)OR_(9a), —C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b),—NR_(9a)S(O)₂R_(9b), —NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c), and—OC(S)CR_(9a)R_(9b)R_(9c). R₁ may be selected from the group consistingof phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl, 1H-indolyl,thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl,1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl, and 1H-indazolyl,wherein the phenyl, 1H-pyrrolopyridinyl, 1H-pyrrolopyridinyl,1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl,2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,or 1H-indazolyl is optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C1-4alkyl, C₁₋₄ alkoxy, halo, halo-substituted-C1-4 alkyl,halo-substituted-C1-4 alkoxy, amino, —O(CH₂)₂NR_(10a)R_(10b),—S(O)₂NR_(10a)R_(10b), —OS(O)₂NR_(10a)R_(10b), and—NR_(10a)S(O)₂R_(10b).

In some embodiments, R₂ is hydrogen.

In some embodiments, R₃ is selected from the group consisting of phenyl,thiophenyl, furanyl, 1H-benzoimidazolyl, quinolinyl, isoquinolinyl,imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl,1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, and thiazolyl,wherein the phenyl, thiophenyl, furanyl, 1H-benzoimidazolyl, quinolinyl,isoquinolinyl, imidazopyridinyl, benzothiophenyl, pyrimidinyl,pyridinyl, 1H-imidazolyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl, orthiazolyl is optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of cyano, hydroxy, C₁-4alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),and wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl.

In some embodiments, R₄ is hydrogen.

In some embodiments, R₅ is selected from the group consisting of C1-10alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl.

In some embodiments, R₅ is selected from the group consisting ofisopropyl, methyl, ethyl, prop-1-en-2-yl, isobutyl, cyclohexyl,sec-butyl, (S)-sec-butyl, (R)-sec-butyl, 1-hydroxypropan-2-yl,(S)-1-hydroxypropan-2-yl, (R)-1-hydroxypropan-2-yl, and nonan-2-yl.

In some embodiments, R₅ is (S)-1-hydroxypropan-2-yl.

In some embodiments, R₅ is (R)-1-hydroxpropan-2-yl.

In some embodiments, R₅ is (S)-sec-butyl.

In some embodiments, R₅ is (R)-sec-butyl.

In some embodiments, R₅ is selected from the group consisting of (i),(ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C1-4 alkenyl, C1-4alkynyl, C2-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl.

In some embodiments, R₅ is selected from the group consisting of:

in some embodiments, R₅ is (ii);

In some embodiments, R₅ is selected from the group consisting of4-methoxybutan-2-yl, (S)-4-methoxybutan-2-yl, (R)-4-methoxybutan-2-yl,4-ethoxybutan-2-yl, (S)-4-ethoxybutan-2-yl, (R)-4-ethoxybutan-2-yl,5-methoxypentan-2-yl, (S)-5-methoxypentan-2-yl,(R)-5-methoxypentan-2-yl, 5-ethoxypentan-2-yl, (S)-5-ethoxypentan-2-yl,(R)-5-ethoxypentan-2-yl, 6-methoxyhexan-2-yl, (S)-6-methoxyhexan-2-yl,(R)-6-methoxyhexan-2-yl, 6-ethoxyhexan-2-yl, (S)-6-ethoxyhexan-2-yl, and(R)-6-ethoxyhexan-2-yl.

In some embodiments, R₅ is (S)-4-methoxybutan-2-yl.

In some embodiments, R₅ is (R)-4-methoxybutan-2-yl.

In some embodiments, R₅ is (S)-5-methoxypentan-2-yl.

In some embodiments, R₅ is (R)-5-methoxypentan-2-yl.

In some embodiments, R₅ is (S)-4-ethoxybutan-2-yl.

In some embodiments, R₅ is (R)-4-ethoxybutan-2-yl.

Particular aryl hydrocarbon receptor antagonists described hereininclude:

as well as salts thereof.

Where the number of any given substituent is not specified, there may beone or more substituents present. For example, “halo-substituted C1-4alkyl” may include one or more of the same or different halogens.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms of carbonyl-containing compounds are alsointended to be included.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, or may be stereoisomeric ordiastereomeric mixtures. As such, one of skill in the art will recognizethat administration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form.

Compounds described herein include, but are not limited to, those setforth above, as well as any of their isomers, such as diastereomers andenantiomers, as well as salts, esters, amides, thioesters, solvates, andpolymorphs thereof, as well as racemic mixtures and pure isomers of thecompounds set forth above.

Synthesis

Substituent Protecting Groups

The synthesis of aryl hydrocarbon receptor antagonists described hereinmay involve the selective protection and deprotection of alcohols,amines, ketones, sulfhydryls or carboxyl functional groups of aprecursor. For example, commonly used protecting groups for aminesinclude carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m-nitrophenyl.Other commonly used protecting groups for amines include amides, such asformamides, acetamides, trifluoroacetamides, sulfonamides,trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, andtert-butylsulfonyl amides. Examples of commonly used protecting groupsfor carboxyls include esters, such as methyl, ethyl, tert-butyl,9-fluorenylmethyl, 2-(trimethylsilyl)ethoxy methyl, benzyl,diphenylmethyl, O-nitrobenzyl, ortho-esters, and halo-esters. Examplesof commonly used protecting groups for alcohols include ethers, such asmethyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl,benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl,2-napthylmethyl, O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl,9-phenylxanthyl, trityl (including methoxy-trityls), and silyl ethers.Examples of commonly used protecting groups for sulfhydryls include manyof the same protecting groups used for hydroxyls. In addition,sulfhydryls can be protected in a reduced form (e.g., as disulfides) oran oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonicamides). Protecting groups can be chosen such that selective conditions(e.g., acidic conditions, basic conditions, catalysis by a nucleophile,catalysis by a Lewis acid, or hydrogenation) are required to removeeach, exclusive of other protecting groups in a compound. The conditionsrequired for the addition of protecting groups to amine, alcohol,sulfhydryl, and carboxyl functionalities and the conditions required fortheir removal are provided in detail, for example, in T. W. Green and P.G. M. Wuts, Protective Groups in Organic Synthesis (2^(nd) Ed.), JohnWiley & Sons, 1991 and P. J. Kocienski, Protecting Groups, Georg ThiemeVerlag, 1994.

Exemplary Synthetic Methods

Aryl hydrocarbon receptor antagonists represented by formula (I) or (II)may be synthesized, for instance, by way of a palladium-catalyzedcoupling reaction, such as a process depicted in Scheme 1, below.

wherein X is C or N, with the proviso that R₂ is absent when X is N;

L is selected from the group consisting of —NR_(7a)(CR_(8a)R_(8b))_(n)—,—O(CR_(8a)R_(8b))_(n)—, —S(O)₀₋₂(CR_(8a)R_(8b))_(n)—, and—(CR_(8a)R_(8b))_(n)—, wherein R_(7a), R_(8a), and R_(8b) are eachindependently selected from the group consisting of hydrogen andoptionally substituted C1-4 alkyl, and each n is independently aninteger from 2 to 6;

R₁ is selected from the group consisting of —S(O)₂NR_(9a)R_(9b),—NR_(9a)C(O)R_(9b), —NR_(9a)C(S)R_(9b), —NR_(9a)C(O)NR_(9b)R_(9c),—C(O)R_(9a), —C(S)R_(9a), —S(O)₀₋₂R_(9a), —C(O)OR_(9a), —C(S)OR_(9a),—C(O)NR_(9a)R_(9b), —C(S)NR_(9a)R_(9b), —NR_(9a)S(O)₂R_(9b),—NR_(9a)C(O)OR_(9b), —OC(O)CR_(9a)R_(9b)R_(9c),—OC(S)CR_(9a)R_(9b)R_(9c), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl, wherein R_(9a), R_(9b), andR_(9c) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl;

R₂ is selected from the group consisting of hydrogen and optionallysubstituted C1-4 alkyl;

R₃ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl;

R₄ is selected from the group consisting of hydrogen and optionallysubstituted C1-4 alkyl;

R₅ is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and

R₆ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl.

For instance, when an organoboron species is employed as a synthon suchas, for example, R₃—B(pin) and/or R₅—B(pin), Suzuki or Suzuki-Miyaurareaction conditions may be used to join the halogenated imidazopyridineor imidazopyrazine precursor with the organoboron R₃ or R₅ synthonspecies in the presence of a Pd catalyst, such as, for examplePd(dppf)Cl₂.

For instance, when L is an amino- or hydroxy-containing linker,Hartwig-Buchwald conditions may be used to join the halogenatedprecursor with the amine or alcohol in the presence of a Pd catalyst, asshown in Scheme 2, below.

Exemplary Hartwig-Buchwald conditions include the use of a Pd catalyst,such as Pd₂(dba)₃, in the presence ofdicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, tBuONa, dioxane,120° C., microwave irradiation. Hartwig-Buchwald reaction conditions areknown in the art and are described, for instance, in Bailey et al.,Bioorganic and Medicinal Chemistry Letters 19:3602-3606 (2009), thedisclosure of which is incorporated herein by reference as it pertainsto conditions useful for the Hartwig-Buchwald amination oretherification.

When L is a thiol, nucleophilic aromatic substitution conditions may beemployed to join the linker to a halogenated precursor, as shown inScheme 3, below.

Nucleophilic aromatic substitution conditions include the use of a baseto deprotonate the thiol shown in the above linker-R₁ pair. Thisreactive modality is particularly useful when the halogenated arylprecursor is activated by the presence of one or moreelectron-withdrawing substituents, (such as nitro, cyano,trifluoromethyl, trichloromethyl, and the like) and/or when X isnitrogen.

Additional amine, hydroxyl, and thiol arylation techniques that may beused to produce the compounds described herein include those describedin Burke, A. J. and Marques, C. S. (eds) (2014) Amine, Phenol, Alcohol,and Thiol Arylation, in Catalytic Arylation Methods: From the AcademicLab to Industrial Processes, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim,Germany, the disclosure of which is incorporated herein by reference asit pertains to processes for chemical synthesis.

A Pd-catalyzed Heck reaction can be used to join olefinic linkers to ahalogenated aryl precursor, as shown in Scheme 4, below.

wherein “═” denotes a carbon-carbon double bond, which can subsequentlybe reduced to yield a saturated alkylene linker using olefin reductionmethods known in the art.

For instances in which L is selected from the group consisting of—C(O)(CR_(8a)R_(8b))_(n)—, —C(S)(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)(CR_(8a)R_(8b))_(n)—, —NR_(7a)C(S)(CR_(8a)R_(8b))_(n)—,—OC(O)(CR_(8a)R_(8b))_(n)—, —OC(S)(CR_(8a)R_(8b))_(n)—,—C(O)NR_(7a)(CR_(8a)R_(8b))_(n)—, —C(S)NR_(7a)(CR_(8a)R_(8b))_(n)—,—C(O)O(CR_(8a)R_(8b))_(n)—, —C(S)O(CR_(8a)R_(8b))_(n)—,—S(O)₂NR_(7a)(CR_(8a)R_(8b))_(n)—, —NR_(7a)S(O)₂(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)NR_(7b)(CR_(8a)R_(8b))_(n)—, and—NR_(7a)C(O)O(CR_(8a)R_(8b))_(n)—, techniques such as acylation,sulfonamidation, and thionation reactions can be employed in order toproduce compounds represented by formulas (I) and (II). Exemplaryacylation, sulfonamidation, and thionation processes that may be used tosynthesize the aryl hydrocarbon receptor antagonists described hereinare depicted in Schemes 5-7, below.

In Scheme 5, LG denotes a nucleofugal leaving group, such as a halogen(for instance, chlorine or bromine), a sulfonate (for instance,tosylate, brosylate, triflate, mesylate, and the like), and otherleaving groups known in the art. In this way, linkers (“L”) containingan amide, ester, ketone, urea, carbamate, or the like in which thecarbonyl carbon is bound directly to the imidazopyridine orimiadzopyrazine ring system can be synthesized.

Similarly, to linkers (“L”) containing a thioketone, thioamide,thioester, and the like can be synthesized by reacting the correspondingketone, amide, or ester with a thionating reagent, as shown in Scheme 6,below.

wherein C(O)Y denotes an amide, ester, ketone, or the like.

Exemplary thionating reagents are known in the art and include, forinstance, Lawesson's reagent, which is described, for example,Jesberger, et al., Synthesis 13:1929-1258 (2003), the disclosure ofwhich is incorporated herein by reference as it pertains to thionationtechniques.

When the linker (“L”) contains a sulfonamide moiety bound to theimidazopyridine or imadazopyrazine ring system, for instance, at thesulfur or nitrogen of the sulfonamide functionality, sulfonamidationtechniques known in the art can be used to produce the correspondingcompound of formula (I) or (II). An exemplary sulfonamidation process isdepicted in Scheme 7, below.

In Scheme 7, LG denotes a nucleofugal leaving group, such as a halogen(for instance, chlorine or bromine), a sulfonate (for instance,tosylate, brosylate, triflate, mesylate, and the like), and otherleaving groups known in the art. In this way, linkers (“L”) containing asulfonamide in which the sulfur or nitrogen of the sulfonamide moiety isbound directly to the imidazopyridine or imiadzopyrazine ring system canbe synthesized.

Stem Cells

In some embodiments, the stem cells of which the population is modified(e.g., expanded) with the compositions and methods described are capableof being expanded upon contacting the aryl hydrocarbon receptorantagonist. In some embodiments, the stem cells are not geneticallymodified stem cells.

In some embodiments, the stem cells are empbryonic stem cells or adultstem cells. In some embodiments, the stem cells are totipotentent stemcells, pluripotent stem cells, multipoteltent stem cells, oligopotentstem cells, or unipotent stem cells. In some embodiments, the stem cellsare tissue-specific stem cells.

In some embodiments, the stem cells are hematopoietic stem cells,intestinal stem cells, osteoblastic stem cells, mesenchymal stem cells(i.e., lung mesenchymal stem cells, bone marrow-derived mesenchymalstromal cells, or bone marrow stromal cells), neural stem cells (i.e.,neuronal dopaminergic stem cells or motor-neuronal stem cells),epithelial stem cells (i.e., lung epithelial stem cells, breastepithelial stem cells, vascular epithelial stem cells, or intestinalepithelial stem cells), cardiac myocyte progenitor stem cells, skin stemcells (i.e., epidermal stem cells or follicular stem cells (hairfollicle stem cells)), skeletal muscle stem cells, adipose stem cells,liver stem cells, induced pluripotent stem cells, umbilical cord stemcells, amniotic fluid stem cells, limbal stem cells, dental pulp stemcells, placental stem cells, myoblasts, endothelial progenitor cells,exfoliated teeth derived stem cells, or hair follicle stem cells.

In some embodiments, the stem cells are hematopoietic stem cells.

In some embodiments, the stem cells are primary stem cells. For example,the stem cells are obtained from bone marrow, adipose tissue, or blood.In some embodiments, the the stem cells are cultured stem cells.

In some embodiments, the stem cells are CD34+ cells. In someembodiments, the stem cells are CD90+ cells. In some embodiments, thestem cells are CD45RA− cells. In some embodiments, the stem cells areCD34+CD90+ cells. In some embodiments, the stem cells are CD34+CD45RA−cells. In some embodiments, the stem cells are CD90+CD45RA− cells. Insome embodiments, the stem cells are CD34+CD90+CD45RA− cells.

In some embodiments, the hematopoietic stem cells are extracted from thebone marrow, mobilized into the peripheral blood and then collected byapheresis, or isolated from umbilical cord blood units.

In some embodiments, the hematopoietic stem cells are CD34+hematopoietic stem cells. In some embodiments, the hematopoietic stemcells are CD90+ hematopoietic stem cells. In some embodiments, thehematopoietic stem cells are CD45RA− hematopoietic stem cells. In someembodiments, the hematopoietic stem cells are CD34+CD90+ hematopoieticstem cells. In some embodiments, the hematopoietic stem cells areCD34+CD45RA− hematopoietic stem cells. In some embodiments, thehematopoietic stem cells are CD90+CD45RA− hematopoietic stem cells. Insome embodiments, the hematopoietic stem cells are CD34+CD90+CD45RA−hematopoietic stem cells.

Methods for Expanding Hematopoietic Stem Cells

In another aspect, the disclosure features a method of producing anexpanded population of hematopoietic stem cells ex vivo, the methodincluding contacting a population of hematopoietic stem cells with thecompound of any one of the above aspects or embodiments in an amountsufficient to produce an expanded population of hematopoietic stemcells.

In another aspect, the disclosure features a method of enriching apopulation of cells with hematopoietic stem cells ex vivo, the methodincluding contacting a population of hematopoietic stem cells with thecompound of any one of the above aspects or embodiments in an amountsufficient to produce a population of cells enriched with hematopoieticstem cells.

In another aspect, the disclosure features a method of maintaining thehematopoietic stem cell functional potential of a population ofhematopoietic stem cells ex vivo for two or more days, the methodincluding contacting a first population of hematopoietic stem cells withthe compound of any one of the above aspects or embodiments, wherein thefirst population of hematopoietic stem cells exhibits a hematopoieticstem cell functional potential after two or more days that is greaterthan that of a control population of hematopoietic stem cells culturedunder the same conditions and for the same time as the first populationof hematopoietic stem cells but not contacted with the compound.

In one embodiment, said method for expanding hematopoietic stem cells,comprises (a) providing a starting cell population comprisinghematopoietic stem cells and (b) culturing said starting cell populationex vivo in the presence of an AHR antagonist agent compound of any oneof the above aspects or embodiments.

The starting cell population comprising hematopoietic stem cells will beselected by the person skilled in the art depending on the envisageduse. Various sources of cells comprising hematopoietic stem cells havebeen described in the art, including bone marrow, peripheral blood,neonatal umbilical cord blood, placenta or other sources such as liver,particularly fetal liver.

The cell population may first be subjected to enrichment or purificationsteps, including negative and/or positive selection of cells based onspecific cellular markers in order to provide the starting cellpopulation. Methods for isolating said starting cell population based onspecific cellular markers may use fluorescent activated cell sorting(FACS) technology also called flow cytometry or solid or insolublesubstrate to which is bound antibodies or ligands that interact withspecific cell surface markers. For example, cells may be contacted witha solid substrate (e.g., column of beads, flasks, magnetic particles)containing the antibodies and any unbound cells are removed. When asolid substrate comprising magnetic or paramagnetic beads is used, cellsbound to the beads can be readily isolated by a magnetic separator.

In one embodiment, said starting cell population is enriched in adesirable cell marker phenotype (e.g., CD34+, CD133+, CD90+) or based onefflux of dyes such as rhodamine, Hoechst or aldehyde dehydrogenaseactivity. In one specific embodiment, said starting cell population isenriched in CD34+ cells. Methods for enriching blood cell population inCD34+ cells include kits commercialized by Miltenyi Biotec (CD34+ directisolation kit, Miltenyi Biotec, Bergisch, Gladbach, Germany) or byBaxter (Isolex 3000).

In some embodiments, the hematopoietic stem cells are CD34+hematopoietic stem cells. In some embodiments, the hematopoietic stemcells are CD90+ hematopoietic stem cells. In some embodiments, thehematopoietic stem cells are CD45RA− hematopoietic stem cells. In someembodiments, the hematopoietic stem cells are CD34+CD90+ hematopoieticstem cells. In some embodiments, the hematopoietic stem cells areCD34+CD45RA− hematopoietic stem cells. In some embodiments, thehematopoietic stem cells are CD90+CD45RA− hematopoietic stem cells. Insome embodiments, the hematopoietic stem cells are CD34+CD90+CD45RA−hematopoietic stem cells.

In some embodiments, the hematopoietic stem cells are mammalian cells,such as human cells. In some embodiments, the human cells are CD34+cells, such as CD34+ cells are CD34+, CD34+CD38−, CD34+CD38−CD90+,CD34+CD38−CD90+CD45RA−, CD34+CD38−CD90+CD45RA−CD49F+, orCD34+CD90+CD45RA− cells.

In some embodiments, the hematopoietic stem cells are obtained fromhuman cord blood, mobilized human peripheral blood, or human bonemarrow. The hematopoietic stem cells may, for example, be freshlyisolated from the human or may have been previously cryopreserved.

The amount of cord blood from a single birth is often inadequate totreat an adult or an older child. One advantage of the expansion methodsusing the compounds of the invention, or an agent capable ofdown-regulating the activity and/or expression of aryl hydrocarbonreceptor and/or a down-stream effector of aryl hydrocarbon receptorpathway, is that it enables the production of a sufficient amount ofhematopoietic stem cells from only one cord blood unit.

Accordingly, in one embodiment, the starting cell population is derivedfrom neonatal umbilical cord blood cells which have been enriched inCD34+ cells. In one related embodiment, said starting cell population isderived from one or two umbilical cord blood Units.

In another embodiment, the starting cell population is derived fromhuman mobilized peripheral blood cells which have been enriched in CD34+cells. In one related embodiment, said starting cell population isderived from human mobilized peripheral blood cells isolated from onlyone patient.

Said starting cell population enriched in CD34+ cells may preferablycontain at least about 50% CD34+ cells, in some embodiments, more thanabout 90% CD34+ cells, and may comprise between 10⁵ and 10⁹ nucleatedcells.

The starting cell population may be used directly for expansion orfrozen and stored for use at a later date.

Conditions for culturing the starting cell population for hematopoieticstem cell expansion will vary depending, inter alia, on the startingcell population, the desired final number of cells, and desired finalproportion of HSCs.

In one embodiment, the culturing conditions comprises the use of othercytokines and growth factors, generally known in the art forhematopoietic stem cell expansion. Such cytokines and growth factorsinclude without limitation IL-1, IL-3, IL-6, IL-11, G-CSF, GM-CSF, SCF,FIT3-L, thrombopoietin (TPO), erythropoeitin, and analogs thereof. Asused herein, “analogs” include any structural variants of the cytokinesand growth factors having the biological activity as the naturallyoccurring forms, including without limitation, variants with enhanced ordecreased biological activity when compared to the naturally occurringforms or cytokine receptor agonists such as an agonist antibody againstthe TPO receptor (for example, VB22B sc(Fv)2 as detailed in patentpublication WO 2007/145227, and the like). Cytokine and growth factorcombinations are chosen to expand HSC and progenitor cells whilelimiting the production of terminally differentiated cells. In onespecific embodiment, one or more cytokines and growth factors areselected from the group consisting of SCF, Flt3-L and TPO. In onespecific embodiment, at least TPO is used in a serum-free medium undersuitable conditions for HSC expansion. In one related embodiment, amixture of IL6, SCF, Flt3-L and TPO is used in the method for expandingHSCs in combination with the compound of the present disclosure.

The expansion of HSC may be carried out in a basal medium, which may besupplemented with mixtures of cytokines and growth factors. A basalmedium typically comprises amino acids, carbon sources, vitamins, serumproteins (e.g. albumin), inorganic salts, divalent cations, buffers andany other element suitable for use in expansion of HSC. Examples of suchbasal medium appropriate for a method of expanding HSC include, withoutlimitation, StemSpan® SFEM—Serum-Free Expansion Medium (StemCellTechnologies, Vancouver, Canada), StemSpan® H3000—Defined Medium(StemCell Technologies, Vancouver, Canada), CellGro® SCGM (CellGenix,Freiburg Germany), StemPro®-34 SFM (Invitrogen).

In one embodiment, the compound of the present disclosure isadministered during the expansion method of said starting cellpopulation under a concentration appropriate for HSC expansion. In onespecific embodiment, said compound or AHR modulating agent isadministered at a concentration comprised between 1 pM and 100 μM, forexample between 10 pM and 10 μM, or between 100 pM and 1 μM.

In one embodiment where starting cell population essentially consists ofCD34+ enriched cells from one or two cord blood units, the cells aregrown under conditions for HSC expansion from about 3 days to about 90days, for example between 7 and 2 days and/or until the indicated foldexpansion and the characteristic cell populations are obtained. In onespecific embodiment, the cells are grown under conditions for HSCexpansion not more than 21 days, 14 days or 7 days.

In one embodiment, the starting cell population is cultured during atime sufficient to reach an absolute number of CD34+ cells of at least10⁵, 10⁶, 10⁷, 10⁸ or 10⁹ cells. In another embodiment, said startingcell population is cultured during a time sufficient for a 10 to 50000fold expansion of CD34+ cells, for example between 100 and 10000 foldexpansion, for examples between 50 and 1000 fold expansion.

The cell population obtained after the expansion method may be usedwithout further purification or may be subject to further purificationor selection steps.

The cell population may then be washed to remove the compound of thepresent disclosure and/or any other components of the cell culture andresuspended in an appropriate cell suspension medium for short term useor in a long-term storage medium, for example a medium suitable forcryopreservation.

Cell Population with Expanded Hematopoietic Stem Cells as Obtained bythe Expansion Method and Therapeutic Compositions

In another aspect, the disclosure features a composition comprising apopulation of hematopoietic stem cells, wherein the hematopoietic stemcells or progenitors thereof have been contacted with the compound ofany one of the above aspects or embodiments, thereby expanding thehematopoietic stem cells or progenitors thereof.

The invention further provides a cell population with expandedhemapoetic stem cells obtainable or obtained by the expansion methoddescribed above. In one embodiment, such cell population is resuspendedin a pharmaceutically acceptable medium suitable for administration to amammalian host, thereby providing a therapeutic composition.

The compound as defined in the present disclosure enables the expansionof HSCs, for example from only one or two cord blood units, to provide acell population quantitatively and qualitatively appropriate forefficient short and long term engraftment in a human patient in needthereof. In one embodiment, the present disclosure relates to atherapeutic composition comprising a cell population with expanded HSCsderived from not more than one or two cord blood units. In oneembodiment, the present disclosure relates to a therapeutic compositioncontaining a total amount of cells of at least about 10⁵, at least about10⁶, at least about 10⁷, at least about 10⁸ or at least about 10⁹ cellswith about 20% to about 100%, for example between about 43% to about80%, of total cells being CD34+ cells. In certain embodiments, saidcomposition contains between 20-100%, for example between 43-80%, oftotal cells being CD34+CD90+CD45RA−.

In some embodiments, the hematopoietic stem cells are CD34+hematopoietic stem cells. In some embodiments, the hematopoietic stemcells are CD90+ hematopoietic stem cells. In some embodiments, thehematopoietic stem cells are CD45RA− hematopoietic stem cells. In someembodiments, the hematopoietic stem cells are CD34+CD90+ hematopoieticstem cells. In some embodiments, the hematopoietic stem cells areCD34+CD45RA− hematopoietic stem cells. In some embodiments, thehematopoietic stem cells are CD90+CD45RA− hematopoietic stem cells. Insome embodiments, the hematopoietic stem cells are CD34+CD90+CD45RA−hematopoietic stem cells.

In some embodiments, the hematopoietic stem cells of the therapeuticcomposition are mammalian cells, such as human cells. In someembodiments, the human cells are CD34+ cells, such as CD34+ cells areCD34+, CD34+CD38−, CD34+CD38−CD90+, CD34+CD38-CD90+CD45RA−,CD34+CD38−CD90+CD45RA−CD49F+, or CD34+CD90+CD45RA− cells.

In some embodiments, the hematopoietic stem cells of the therapeuticcomposition are obtained from human cord blood, mobilized humanperipheral blood, or human bone marrow. The hematopoietic stem cellsmay, for example, be freshly isolated from the human or may have beenpreviously cryopreserved.

Methods of Treatment

As described herein, hematopoietic stem cell transplant therapy can beadministered to a subject in need of treatment so as to populate orrepopulate one or more blood cell types, such as a blood cell lineagethat is deficient or defective in a patient suffering from a stem celldisorder. Hematopoietic stem and progenitor cells exhibit multi-potency,and can thus differentiate into multiple different blood lineagesincluding, but not limited to, granulocytes (e.g., promyelocytes,neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes,erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producingmegakaryocytes, platelets), monocytes (e.g., monocytes, macrophages),dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NKcells, B-cells and T-cells). Hematopoietic stem cells are additionallycapable of self-renewal, and can thus give rise to daughter cells thathave equivalent potential as the mother cell, and also feature thecapacity to be reintroduced into a transplant recipient whereupon theyhome to the hematopoietic stem cell niche and re-establish productiveand sustained hematopoiesis. Thus, hematopoietic stem and progenitorcells represent a useful therapeutic modality for the treatment of awide array of disorders in which a patient has a deficiency or defect ina cell type of the hematopoietic lineage. The deficiency or defect maybe caused, for example, by depletion of a population of endogenous cellsof the hematopoietic system due to administration of a chemotherapeuticagent (e.g., in the case of a patient suffering from a cancer, such as ahematologic cancer described herein). The deficiency or defect may becaused, for example, by depletion of a population of endogenoushematopoietic cells due to the activity of self-reactive immune cells,such as T lymphocytes or B lymphocytes that cross-react with selfantigens (e.g., in the case of a patient suffering from an autoimmunedisorder, such as an autoimmune disorder described herein). Additionallyor alternatively, the deficiency or defect in cellular activity may becaused by aberrant expression of an enzyme (e.g., in the case of apatient suffering from various metabolic disorders, such as a metabolicdisorder described herein).

Thus, hematopoietic stem cells can be administered to a patientdefective or deficient in one or more cell types of the hematopoieticlineage in order to re-constitute the defective or deficient populationof cells in vivo, thereby treating the pathology associated with thedefect or depletion in the endogenous blood cell population.Hematopoietic stem and progenitor cells can be used to treat, e.g., anon-malignant hemoglobinopathy (e.g., a hemoglobinopathy selected fromthe group consisting of sickle cell anemia, thalassemia, Fanconi anemia,aplastic anemia, and Wiskott-Aldrich syndrome). In these cases, forexample, a population of hematopoietic stem cells may be expanded exvivo by culturing the cells in the presence of an aryl hydrocarbonreceptor antagonist described herein. The hematopoietic stem cells thusexpanded may then be administered to a patient, where the cells may hometo a hematopoietic stem cell niche and re-constitute a population ofcells that are damaged or deficient in the patient.

Hematopoietic stem or progenitor cells mobilized to the peripheral bloodof a subject may be withdrawn (e.g., harvested or collected) from thesubject by any suitable technique. For example, the hematopoietic stemor progenitor cells may be withdrawn by a blood draw. In someembodiments, hematopoietic stem or progenitor cells mobilized to asubject's peripheral blood as contemplated herein may be harvested(i.e., collected) using apheresis. In some embodiments, apheresis may beused to enrich a donor's blood with mobilized hematopoietic stem orprogenitor cells.

Additionally or alternatively, hematopoietic stem and progenitor cellscan be used to treat an immunodeficiency, such as a congenitalimmunodeficiency. Additionally or alternatively, the compositions andmethods described herein can be used to treat an acquiredimmunodeficiency (e.g., an acquired immunodeficiency selected from thegroup consisting of HIV and AIDS). In these cases, for example, apopulation of hematopoietic stem cells may be expanded ex vivo byculturing the cells in the presence of an aryl hydrocarbon receptorantagonist described herein. The hematopoietic stem cells thus expandedmay then be administered to a patient, where the cells may home to ahematopoietic stem cell niche and re-constitute a population of immunecells (e.g., T lymphocytes, B lymphocytes, NK cells, or other immunecells) that are damaged or deficient in the patient.

Hematopoietic stem and progenitor cells can also be used to treat ametabolic disorder (e.g., a metabolic disorder selected from the groupconsisting of glycogen storage diseases, mucopolysaccharidoses,Gaucher's Disease, Hurlers Disease, sphingolipidoses, Sly Syndrome,alpha-Mannosidosis, X-ALD, Aspartylglucosaminuria, Wolman Disease, lateinfantile metachromatic leukodystrophy, Niemann Pick Type C disease,Niemann Pick Type B disease, Juvenile Tay Sachs, Infantile Tay Sachs,Juvenile Sandhoff, Infantile Sandhoff, GM1 gangliosidosis, MPSIV(Morquio), Presymptomatic or milder forms of globoid cellleukodystrophy, infantile Krabbe when newborn and asymptomatic, earlydiagnosis fucosidosis, Fabry, MPSIS, MPSIH/S, MPSII, MPSVI inconjunction with ERT or where alloantibodies attenuate efficacy of ERT,Pompe where alloantibodies attenuate efficacy of ERT, Mucolipidosis II,and metachromatic leukodystrophy). In these cases, for example, apopulation of hematopoietic stem cells may be expanded ex vivo byculturing the cells in the presence of an aryl hydrocarbon receptorantagonist described herein. The hematopoietic stem cells thus expandedmay then be administered to a patient, where the cells may home to ahematopoietic stem cell niche and re-constitute a population ofhematopoietic cells that are damaged or deficient in the patient.

Additionally or alternatively, hematopoietic stem or progenitor cellscan be used to treat a malignancy or proliferative disorder, such as ahematologic cancer or myeloproliferative disease. In the case of cancertreatment, for example, a population of hematopoietic stem cells may beexpanded ex vivo by culturing the cells in the presence of an arylhydrocarbon receptor antagonist described herein. The hematopoietic stemcells thus expanded may then be administered to a patient, where thecells may home to a hematopoietic stem cell niche and re-constitute apopulation of cells that are damaged or deficient in the patient, suchas a population of hematopoietic cells that is damaged or deficient dueto the administration of one or more chemotherapeutic agents to thepatient. In some embodiments, hematopoietic stem or progenitor cells maybe infused into a patient in order to repopulate a population of cellsdepleted during cancer cell eradication, such as during systemicchemotherapy. Exemplary hematological cancers that can be treated by wayof administration of hematopoietic stem and progenitor cells inaccordance with the compositions and methods described herein are acutemyeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia,chronic lymphoid leukemia, multiple myeloma, diffuse large B-celllymphoma, and non-Hodgkin's lymphoma, as well as other cancerousconditions, including neuroblastoma.

Additional diseases that can be treated by the administration ofhematopoietic stem and progenitor cells to a patient include, withoutlimitation, adenosine deaminase deficiency and severe combinedimmunodeficiency, hyper immunoglobulin M syndrome, Chediak-Higashidisease, hereditary lymphohistiocytosis, osteopetrosis, osteogenesisimperfecta, storage diseases, thalassemia major, systemic sclerosis,systemic lupus erythematosus, multiple sclerosis, and juvenilerheumatoid arthritis.

In addition, administration of hematopoietic stem and progenitor cellscan be used to treat autoimmune disorders. In some embodiments, uponinfusion into a patient, transplanted hematopoietic stem and progenitorcells may home to a stem cell niche, such as the bone marrow, andestablish productive hematopoiesis. This, in turn, can re-constitute apopulation of cells depleted during autoimmune cell eradication, whichmay occur due to the activity of self-reactive lymphocytes (e.g.,self-reactive T lymphocytes and/or self-reactive B lymphocytes).Autoimmune diseases that can be treated by way of administeringhematopoietic stem and progenitor cells to a patient include, withoutlimitation, psoriasis, psoriatic arthritis, Type 1 diabetes mellitus(Type 1 diabetes), rheumatoid arthritis (RA), human systemic lupus(SLE), multiple sclerosis (MS), inflammatory bowel disease (IBD),lymphocytic colitis, acute disseminated encephalomyelitis (ADEM),Addison's disease, alopecia universalis, ankylosing spondylitisis,antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmunehemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease(AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmuneoophoritis, Balo disease, Behcet's disease, bullous pemphigoid,cardiomyopathy, Chagas' disease, chronic fatigue immune dysfunctionsyndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy,Crohn's disease, cicatrical pemphigoid, coeliac sprue-dermatitisherpetiformis, cold agglutinin disease, CREST syndrome, Degos disease,discoid lupus, dysautonomia, endometriosis, essential mixedcryoglobulinemia, fibromyalgia-fibromyositis, Goodpasture's syndrome,Grave's disease, Guillain-Barre syndrome (GBS), Hashimoto's thyroiditis,Hidradenitis suppurativa, idiopathic and/or acute thrombocytopenicpurpura, idiopathic pulmonary fibrosis, IgA neuropathy, interstitialcystitis, juvenile arthritis, Kawasaki's disease, lichen planus, Lymedisease, Meniere disease, mixed connective tissue disease (MCTD),myasthenia gravis, neuromyotonia, opsoclonus myoclonus syndrome (OMS),optic neuritis, Ord's thyroiditis, pemphigus vulgaris, perniciousanemia, polychondritis, polymyositis and dermatomyositis, primarybiliary cirrhosis, polyarteritis nodosa, polyglandular syndromes,polymyalgia rheumatica, primary agammaglobulinemia, Raynaud phenomenon,Reiter s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjögren'ssyndrome, stiff person syndrome, Takayasu's arteritis, temporalarteritis (also known as “giant cell arteritis”), ulcerative colitis,collagenous colitis, uveitis, vasculitis, vitiligo, vulvodynia (“vulvarvestibulitis”), and Wegener s granulomatosis.

Hematopoietic stem cell transplant therapy may additionally be used totreat neurological disorders, such as Parkinson's disease, Alzheimer'sdisease, multiple sclerosis, Amyotrophic lateral sclerosis, Huntington'sdisease, mild cognitive impairment, amyloidosis, AIDS-related dementia,encephalitis, stroke, head trauma, epilepsy, mood disorders, anddementia. As described herein, upon transplantation into a patient,hematopoietic stem cells may migrate to the central nervous system anddifferentiate into, for example, microglial cells, therebyre-constituting a population of cells that may be damaged or deficientin a patient suffering from a neurological disorder. In these cases, forexample, a population of hematopoietic stem cells may be expanded exvivo by culturing the cells in the presence of an aryl hydrocarbonreceptor antagonist described herein. The hematopoietic stem cells thusexpanded may then be administered to a patient suffering from aneurological disorder, where the cells may home to the central nervoussystem, such as the brain of the patient, and re-constitute a populationof hematopoietic cells (e.g., microglial cells) that are damaged ordeficient in the patient.

As described herein, hematopoietic stem cell transplant therapy can beadministered to a subject in need of treatment so as to populate orrepopulate one or more blood cell types, such as a blood cell lineagethat is deficient or defective in a patient suffering from a stem celldisorder. Hematopoietic stem and progenitor cells exhibit multi-potency,and can thus differentiate into multiple different blood lineagesincluding, in one embodiment, microglia.

The methods disclosed herein for treating disorders in a subject in needthereof comprise the administration of an expanded population ofhematopoietic stem cells to a subject in need thereof. In oneembodiment, the number of expanded hematopoietic stem cells administeredto the subject is equal to or greater than the amount of hematopoieticstem cells needed to achieve a therapeutic benefit. In one embodiment,the number of expanded hematopoietic stem cells administered to thesubject is greater than the amount of hematopoietic stem cells needed toachieve a therapeutic benefit. In one embodiment, the therapeuticbenefit achieved is proportional to the number of expanded hematopoieticstem cells that are administered.

A dose of the expanded hematopoietic stem cell composition of thedisclosure is deemed to have achieved a therapeutic benefit if italleviates a sign or a symptom of the disease. The sign or symptom ofthe disease may comprise one or more biomarkers associated with thedisease, or one or more clinical symptoms of the disease.

For example, administration of the expanded hematopoietic stem cellcomposition may result in the reduction of a biomarker that is elevatedin individuals suffering from the disease, or elevate the level of abiomarker that is reduced in individuals suffering from the disease.

For example, administering the expanded hematopoietic stem cellcomposition of the disclosure may elevate the level of an enzyme that isreduced in an individual suffering from a metabolic disorder. Thischange in biomarker level may be partial, or the level of the biomarkermay return to levels normally seen in healthy individuals.

Selection of Donors and Patients

In some embodiments, the patient is the donor. In such cases, withdrawnhematopoietic stem or progenitor cells may be re-infused into thepatient, such that the cells may subsequently home hematopoietic tissueand establish productive hematopoiesis, thereby populating orrepopulating a line of cells that is defective or deficient in thepatient (e.g., a population of megakaryocytes, thrombocytes, platelets,erythrocytes, mast cells, myeoblasts, basophils, neutrophils,eosinophils, microglia, granulocytes, monocytes, osteoclasts,antigen-presenting cells, macrophages, dendritic cells, natural killercells, T-lymphocytes, and B-lymphocytes). In this scenario, thetransplanted hematopoietic stem or progenitor cells are least likely toundergo graft rejection, as the infused cells are derived from thepatient and express the same HLA class I and class II antigens asexpressed by the patient.

Alternatively, the patient and the donor may be distinct. In someembodiments, the patient and the donor are related, and may, forexample, be HLA-matched. As described herein, HLA-matcheddonor-recipient pairs have a decreased risk of graft rejection, asendogenous T cells and NK cells within the transplant recipient are lesslikely to recognize the incoming hematopoietic stem or progenitor cellgraft as foreign, and are thus less likely to mount an immune responseagainst the transplant. Exemplary HLA-matched donor-recipient pairs aredonors and recipients that are genetically related, such as familialdonor-recipient pairs (e.g., sibling donor-recipient pairs).

In some embodiments, the patient and the donor are HLA-mismatched, whichoccurs when at least one HLA antigen, in particular with respect toHLA-A, HLA-B and HLA-DR, is mismatched between the donor and recipient.To reduce the likelihood of graft rejection, for example, one haplotypemay be matched between the donor and recipient, and the other may bemismatched.

Administration and Dosing of Hematopoietic Stem or Progenitor Cells

Hematopoietic stem and progenitor cells described herein may beadministered to a subject, such as a mammalian subject (e.g., a humansubject) suffering from a disease, condition, or disorder describedherein, by one or more routes of administration. For instance,hematopoietic stem cells described herein may be administered to asubject by intravenous infusion. Hematopoietic stem cells may beadministered at any suitable dosage. Non-limiting examples of dosagesinclude about 1×10⁵ CD34+ cells/kg of recipient to about 1×10⁸ CD34+cells/kg (e.g., from about 2×10⁵ CD34+ cells/kg to about 9×10⁷ CD34+cells/kg, from about 3×10⁵ CD34+ cells/kg to about 8×10⁷ CD34+ cells/kg,from about 4×10⁵ CD34+ cells/kg to about 7×10⁷ CD34+ cells/kg, fromabout 5×10⁵ CD34+ cells/kg to about 6×10⁷ CD34+ cells/kg, from about5×10⁵ CD34+ cells/kg to about 1×10⁸ CD34+ cells/kg, from about 6×10⁵CD34+ cells/kg to about 1×10⁸ CD34+ cells/kg, from about 7×10⁵ CD34+cells/kg to about 1×10⁸ CD34+ cells/kg, from about 8×10⁵ CD34+ cells/kgto about 1×10⁸ CD34+ cells/kg, from about 9×10⁵ CD34+ cells/kg to about1×10⁸ CD34+ cells/kg, from about 1×10⁷ CD34+ cells/kg to about 1×10⁸CD34+ cells/kg, or from about 1×10⁶ CD34+ cells/kg to about 1×10⁷ CD34+cells/kg, among others).

Hematopoietic stem or progenitor cells and pharmaceutical compositionsdescribed herein may be administered to a subject in one or more doses.When multiple doses are administered, subsequent doses may be providedone or more days, weeks, months, or years following the initial dose.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a description of how the compositions and methodsdescribed herein may be used, made, and evaluated, and are intended tobe purely exemplary and are not intended to limit the scope of what theinventors regard as their invention.

Example 1. Synthesis of Compound (5)

Compound (5) can be synthesized, for example, using a Hartwig-Buchwaldamination process that includes coupling a halogenated imidazopyridineprecursor to a protected 2-aminoethyl indole, as shown in Scheme 8,below.

Deprotection of the ensuing adduct, for instance, using conventionaldeprotection methods known in the art, can yield compound (5).

Alternatively, the tandem amination-hydrolysis procedure outline inScheme 9, below, may be used to synthesize compound (5).

Example 2. Synthesis of Compound (16)

In a manner similar to that described in Example 1, compound (16) can besynthesized by way of a Hartwig-Buchwald process, followed by a Suzukicoupling and indole deprotection, as shown in Scheme 10, below.

Example 3. Capacity of Compounds (5) and (16) to Expand HematopoieticStem Cells

To determine the ability of compounds (5) and (16) to inhibit theactivity of the aryl hydrocarbon receptor and to induce theproliferation of hematopoietic stem cells, a series of HSC expansionexperiments were conducted. In the first experiment, compounds (5) and(16) were assessed for their capacity to attenuate aryl hydrocarbonreceptor signaling. To this end, HepG2 hepatocytes were transientlytransfected with a luciferase reporter construct under the control of apromoter responsive to aryl hydrocarbon receptor signal transduction.The cells were plated at a density of 25,000 cells per well in amicrotiter plate. The HepG2 cells were immediately treated with compound(5) or (16) in the absence (FIG. 1) or presence (FIG. 2) of the arylhydrocarbon receptor agonist, VAF347 (80 nM). Luciferase activity wassubsequently analyzed six hours after plating.

As shown in FIGS. 1 and 2, compounds (5) and (16) were capable ofsuppressing aryl hydrocarbon receptor activity even in the presence ofthe activator VAF347.

To assess the ability of compounds (5) and (16) to induce theproliferation of hematopoietic stem cells, a population of mononuclearperipheral blood cells enriched in CD34+ cells were plated at a densityof 2,350 cells per well (50 μL) in a microtiter plate in the presence ofeach compound. The percentage of CD34+ hematopoietic stem cells wasassessed seven days following the initial plating. The results of thisexperiment are reported in FIG. 3. As shown therein, compounds (5) and(16) were capable of potentiating hematopoietic stem cell growth in adose-dependent manner. The compounds of formula (I) and (II) describedherein can thus be used to expand hematopoietic stem cells ex vivo inorder to obtain sufficient quantities of such cells for in vivoapplications.

Surprisingly, compounds (5) and (16) were capable of promotinghematopoietic stem cell expansion with a potency greater than thatreported for StemRegeninl (SR1), which is described, for example, inU.S. Pat. No. 8,927,281, which is incorporated herein by reference. Thisdifference in biological activity is expected to have a significantclinical benefit, as a reduced quantity of aryl hydrocarbon receptorantagonists according to formulas (I) and (II) described herein relativeto SR1 may be used to prepare an amplified population of hematopoieticstem cells suitable for transplantation to a patient in need thereof(for instance, as described in Example 4, below).

Example 4. Administration of Hematopoietic Stem Cells to a Human Patientin Need Thereof

Using the methods disclosed herein, a population of hematopoietic stemcells that have been expanded ex vivo using the aryl hydrocarbonreceptor antagonists of formula (I) or (II) can be administered to ahuman patient in need of hematopoietic stem cell transplant therapy.Prior to the transplantation, a population of hematopoietic stem cellsmay be cultured in the presence of the aryl hydrocarbon receptorantagonist for one or more days (e.g., for one, two, three, four, five,six, seven, eight, nine, ten, or more days, replenishing culture mediumas needed). The hematopoietic stem cell population may be expanded to1×10⁶ to 1×10¹² hematopoietic stem cells prior to infusion into thepatient in need of transplant therapy.

Following the conclusion of the expansion process, the patient mayreceive an infusion (e.g., an intravenous infusion) of the expanded,exogenous hematopoietic stem cells, such as from a practitioner thatperformed the ex vivo expansion or from a different physician. Thepatient may then be administered an infusion of autologous, syngeneic,or allogeneic hematopoietic stem cells, for instance, at a dosage offrom 1×10³ to 1×10⁹ hematopoietic stem cells/kg. The engraftment of thehematopoietic stem cell transplant may be monitored, for example, bydetecting an increase in concentration of hematopoietic stem cells orcells of the hematopoietic lineage (such as megakaryocytes,thrombocytes, platelets, erythrocytes, mast cells, myoblasts, basophils,neutrophils, eosinophils, microglia, granulocytes, monocytes,osteoclasts, antigen-presenting cells, macrophages, dendritic cells,natural killer cells, T-lymphocytes, and B-lymphocytes) in a bloodsample isolated from the patient following administration of thetransplant. This analysis may be conducted, for example, from 1 hour to6 months, or more, following hematopoietic stem cell transplant therapy(e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22hours, 23 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23weeks, 24 weeks, or more). A finding that the concentration ofhematopoietic stem cells or cells of the hematopoietic lineage hasincreased (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 500%, or more) following thetransplant therapy relative to the concentration of the correspondingcell type prior to transplant therapy provides one indication that thetransplantation therapy is successful.

Example 5. Engraftment of Microglial Cells in the Central Nervous SystemFollowing Hematopoietic Stem Cell Transplant

To investigate the ability of hematopoietic stem cells to differentiateinto microglial cells and subsequently engraft in central nervous systemtissue, such as the brain of a hematopoietic stem cell transplantrecipient, a series of experiments were conducted in which humanhematopoietic stem cells were first expanded ex vivo in the presence ofan aryl hydrocarbon receptor antagonist (compound (16) or compound (24))and were subsequently transplanted into NSG mice, in accordance with thescheme shown in FIG. 4. The frequency of human CD45+ cells in theperipheral blood of the mice was then determined, as well as the profileof microglial cells in the brain tissue using flow cytometry andimmunohistochemistry techniques.

As shown in FIGS. 5A and 5B, upon transplantation of hematopoietic stemcells expanded ex vivo in the presence of compound (16), NSG miceexhibited an increased frequency of hCD45+ cells in peripheral blood, aswell as an increased engraftment of hCD45+CD11b+ microglial cells in thebrain. Similar results were obtained upon transplantation ofhematopoietic stem cells expanded ex vivo in the presence of compound(24), as shown in FIGS. 6A and 6B.

Collectively, these data demonstrate the ability of hematopoietic stemcells expanded in the presence of aryl hydrocarbon receptor antagonistsdescribed herein to promote the engraftment of microglial cells incentral nervous system tissue of a hematopoietic stem cells transplantrecipient. These findings provide further evidence that hematopoieticstem cell transplantation can be used to treat a wide array ofneurological disorders, including Parkinson's disease, Alzheimer'sdisease, multiple sclerosis, Amyotrophic lateral sclerosis, Huntington'sdisease, mild cognitive impairment, amyloidosis, AIDS-related dementia,encephalitis, stroke, head trauma, epilepsy, mood disorders, anddementia, among others.

Materials and Methods

Cord Blood Expansion and Transplantation

Approximately 60,000 cord blood CD34+ cells were seeded in T25 flasks ata final volume of 12 mL in HSC growth media (SFEM supplemented withPen/Strep, 50 ng/mL FLT3L, TPO, SCF, and IL-6). Flasks were incubatedfor 10 days at 37° C./5% CO₂. Cells were cultured in the presence of 500nM of AHR antagonist, where indicated. Cells were transferred to alarger flask when needed to maintain cells at a density less than 1×10⁶cells/mL throughout the culture period.

At the time of thaw, an equal number of cells to the starting cellcultures were injected into NSG mice, sublethally irradiated (200 cGy)24 hours prior to injection. After 10 days of culture, the entireprogeny of the cultures was injected into NSG mice. Peripheral blood washarvested by retro-orbital bleeding at approximately weeks 4 and 8 or bycardiac puncture at week 12 and chimerism was assessed by flow cytometryusing antibodies against hCD45, mCD45, hCD33, hCD19, hCD3 and aviability dye.

Brain Harvesting and Processing

At 3 months, brains were harvested. 1 hemisphere was fixed in formalin,embedded, and used for immunohistochemistry. The other hemisphere wascrushed in Dounce buffer (15 mM HEPES/0.5% glucose in phenol red-freeHBSS) and filtered through a 40 μM filter to create a single cellsuspension and resuspended in 900 μL 0.5% BSA/PBS. Myelin was depletedfrom brain samples, per manufacturer's instructions, by incubating with100 μL myelin removal beads (Miltenyi Biotec), incubating for 15 minutesat 4° C., washing with PBS, and resuspending in 1 mL MACS Buffer priorto deletion on an AutoMACs Pro.

Flow Cytometric Detection of Microglia

Myelin-depleted samples were resuspended in 100 μL PBS and stained withantibodies against hCD45, mCD45, CD11b, CD19, CD3, and 7-AAD viabilitydye. Cells were washed once in PBS and resuspended in 300 μL finalvolume. The entire sample was acquired by flow cytometry (BD Celesta) toquantitate the number of microglia per brain hemisphere.

Immunohistochemical Detection of Microglia

Embedded brains were sectioned at approximately 5 microns and stainedwith Ku80 (brown) and lba-1 (red) primary antibodies). Mouse brains wereanalyzed from each transplanted mouse and five levels were analyzedeach. Glass slides were scanned at 20× using an Aperio AT2 whole slidescanner. Image analysis was performed on the digital slide images usingVisiopharm software.

Example 6. Synthesis of Compound (24)

In a manner similar to that described in Example 1 and Example 2,compound (24) can be synthesized by way of an arene iodination andHartwig-Buchwald process, followed by a first Suzuki coupling, a secondSuzuki coupling and alkene reduction by catalytic hydrogenation overpalladium as shown in Scheme 11, below.

6-(5-fluoropyridin-3-yl)-N-[2-(1H-indol-3-yl)ethyl]-3-(3-methoxy-1-methylpropyl)imidazo[1,2-a]pyrazin-8-amine,Compound (24) was isolated as a white solid. FIG. 7 sets forth a ¹H-NMRspectrum (d6-DMSO) consistent with the structure. HPLC analysis gave97.93% Area at 254 nm and 97.65% Area at 210 nm; Retention time: 3.765min; HPLC conditions: Agilent 1100 HPLC. Zorbax Eclipse XDBC18 50×4.6 mm1.8 micron column. Solvent A: Water (0.1% TFA); Solvent B: Acetonitrile(0.07% TFA). Gradient: 95% A to 95% B over 5 min; hold for 1 min;recycle over 1 min; 30 s hold. UV Detection: 210 and 254 nm with noreference. Column temperature: 30° C. Mass spectrum was consistent withstructure MS (ESI+) for C₂₆H₂₇FN₆O m/z 459.1 (M+H)+; MS (ESI−) forC₂₆H₂₇FN₆O m/z 457.2 (M−H)−.

Preparative HPLC AD-H (2×25 cm) 25% methanol/CO₂, 100 bar, 65 mL/min,220 nm, inj vol.: 0.5 mL, 20 mg/mL methanol:DCM and analytical HPLC AD-H(25×0.46 cm) 35% methanol/CO₂, 100 bar 3 mL/min, 220, 254 and 280 nmallowed for the resolution of distinct enatiomeric peaks for Compound(24). FIG. 8 sets forth a ¹H-NMR spectrum (d6-DMSO) consistent with thestructure isolated as peak 1. FIG. 9 sets forth a ¹H-NMR spectrum(d6-DMSO) consistent with the structure isolated as peak 2.

Example 7. Synthesis of Compound (27)

In a manner similar to that described in Example 6, compound (27) can besynthesized by way of a first Suzuki coupling, and second Suzukicoupling and alkene reduction by catalytic hydrogenation over palladiumas shown in Scheme 12, below.

6-(5-fluoropyridin-3-yl)-N-[2-(1H-indol-3-yl)ethyl]-3-(4-methoxy-1-methylbutyl)imidazo[1,2-a]pyrazin-8-amine,Compound (27) was isolated as a white solid. FIG. 10 sets forth a ¹H-NMRspectrum (CDCl₃) consistent with the structure. HPLC analysis gave 98.0%Area at 254 nm and 97.2% Area at 210 nm; Retention time: 3.670 min; HPLCconditions: Agilent 1100 HPLC. Zorbax Eclipse XDBC18; 50×4.6 mm 1.8micron column. Solvent A: Water (0.1% TFA); Solvent B: Acetonitrile(0.07% TFA). Gradient: 95% A to 95% B over 5 min; hold for 1 min;recycle over 1 min; 30 s hold. UV Detection: 210 and 254 nm with noreference. Column temperature: 30° C. Mass Spectrum was consistent withstructure MS (ESI+) for C₂₇H₂₉FN₆O m/z 473.1 (M+H)+; MS (ESI−) forC₂₇H₂₉FN₆O m/z 471.2 (M−H)−

Example 8. Synthesis of Compound (28)

In a manner similar to that described in Example 6 and Example 7,compound (28) can be synthesized by way of a first Suzuki coupling, andsecond Suzuki coupling and alkene reduction by catalytic hydrogenationover palladium as shown in Scheme 13, below.

3-(3-ethoxy-1-methylpropyl)-6-(5-fluoropyridin-3-yl)-N-[2-(1H-indol-3-yl)ethyl]imidazo[1,2-a]pyrazin-8-amine,Compound (28) was isolated as an off-white solid. FIG. 11 sets forth a¹H-NMR spectrum (CDCl₃) consistent with the structure. HPLC analysisgave 99.3% Area at 254 nm and 99.0% Area at 210 nm; Retention time:3.757 min; HPLC conditions: Agilent 1100 HPLC. Zorbax Eclipse XDBC18;50×4.6 mm 1.8 micron column. Solvent A: Water (0.1% TFA); Solvent B:Acetonitrile (0.07% TFA). Gradient: 95% A to 95% B over 5 min; hold for1 min; recycle over 1 min; 30 s hold. UV Detection: 210 and 254 nm withno reference. Column temperature: 30° C. Mass spectrum was consistentwith structure MS (ESI+) for C₂₇H₂₉FN₆O m/z 473.1 (M+H)+; MS (ESI−) forC₂₇H₂₉FN₆O m/z 471.2 (M−H)−.

Suitable substrates may be provided for the first Suzuki coupling in thesynthesis of compound (24), compound (27), and compound (28) in Example6, Example 7, and Example 8, respectively, by alkylation of a suitablealkynyl alcohol and borylation of the alkyne as shown in Scheme 14,below.

Example 9. Evaluation of AHR Antagonists

To determine the activity of a scale-up batch of Compound (24),individual enantiomers, and two derivatives Compound (27) and Compound(28) were evaluated for i) the ability to expand CD34+ hematopoieticstem/progenitor cells and ii) AHR antagonist activity. The compoundswere compared to control AHR antagonist SR1, an additional control AHRantagonist, and stored sample of Compound (24)

CD34+ Frequency and Number

Methods—mobilized peripheral blood CD34+ cells were cultured in thepresence of compound, in dose response beginning at 10 μM. CD34+ cellfrequency and number was assessed at day 7 by flow cytometry. Allsynthesized compounds show equivalent expansion capabilities if notgreater than SR1.

TABLE 1 CD34+ Frequency and Number Compound EC50 (μM) SR1 0.112 ControlAHR Antagonist 0.001 Compound (24) - storage (racemic) 0.007 Compound(24) - scale-up (racemic) 0.007 Compound (24) - Enantiomer Peak 1 0.011Compound (24) - Enantiomer Peak 2 0.004 Compound (28) 0.010 Compound(27) 0.008AHR Antagonist Assay

Methods—HepG2 cells transiently transfected with the pGudLuc6.1 plasmidwere thawed and 25,000 cells were plated per well and immediatelytreated the AHR agonist VAF347 (fixed at 40 nM) and/or the indicated AHRantagonists. Luciferase activity was measured 24 hours post-culture,corresponding to endogenous AHR antagonist activity (without VAF347,FIG. 14) or in the presence of VAF347 (FIG. 15). All synthesizedcompounds show equivalent AHR antagonist activity if not greater thanSR1.

TABLE 2 Endogenous AHR Antagonist Activity Compound EC50 (μM) SR1 0.033Control AHR Antagonist 0.0009 Compound (24) - storage (racemic) 0.001Compound (24) - scale-up (racemic) ND Compound (24) - Enantiomer Peak 10.001 Compound (24) - Enantiomer Peak 2 0.0004 Compound (28) 0.002Compound (27) 0.002

TABLE 3 AHR Antagonist Activity in the Presence of VAF347 Compound EC50(μM) SR1 0.193 Control AHR Antagonist 0.014 Compound (24) - storage(racemic) 0.013 Compound (24) - scale-up (racemic) 0.011 Compound (24) -Enantiomer Peak 1 0.012 Compound (24) - Enantiomer Peak 2 0.006 Compound(28) 0.030 Compound (27) 0.009

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from theinvention that come within known or customary practice within the art towhich the invention pertains and may be applied to the essentialfeatures hereinbefore set forth, and follows in the scope of the claims.

Other embodiments are within the claims.

The invention claimed is:
 1. A method of producing an expandedpopulation of hematopoietic stem cells ex vivo, comprising contacting apopulation of hematopoietic stem cells with a compound represented byformula (I) or (II):

wherein L is selected from the group consisting of—NR_(7a)(CR_(8a)R_(8b))_(n)—, —O(CR_(8a)R_(8b))_(n)—,—C(O)(CR_(8a)R_(8b))_(n)—, —C(S)(CR_(8a)R_(8b))_(n)—,—S(O)₀₋₂(CR_(8a)R_(8b))_(n)—, —(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)(CR_(8a)R_(8b))_(n)—, —NR_(7a)C(S)(CR_(8a)R_(8b))_(n)—,—OC(O)(CR_(8a)R_(8b))_(n)—, —OC(S)(CR_(8a)R_(8b))_(n)—,—C(O)NR_(7a)(CR_(8a)R_(8b))_(n)—, —C(S)NR_(7a)(CR_(8a)R_(8b))_(n)—,—C(O)O(CR_(8a)R_(8b))_(n)—, —C(S)O(CR_(8a)R_(8b))_(n)—,—S(O)₂NR_(7a)(CR_(8a)R_(8b))_(n)—, —NR_(7a)S(O)₂(CR_(8a)R_(8b))_(n)—,—NR_(7a)C(O)NR_(7b)(CR_(8a)R_(8b))_(n)—, and—NR_(7a)C(O)O(CR_(8a)R_(8b))_(n)—, wherein R_(7a), R_(7b), R_(8a), andR_(8b) are each independently selected from the group consisting ofhydrogen and optionally substituted C1-4 alkyl, and each n isindependently an integer from 2 to 6; R₁ is selected from the groupconsisting of —S(O)₂NR_(9a)R_(9b), —NR_(9a)C(O)R_(9b),—NR_(9a)C(S)R_(9b), —NR_(9a)C(O)NR_(9b)R_(9c), —C(O)R_(9a), —C(S)R_(9a),—S(O)₀₋₂R_(9a), —C(O)OR_(9a), —C(S)OR_(9a), —C(O)NR_(9a)R_(9b),—C(S)NR_(9a)R_(9b), —NR_(9a)S(O)₂R_(9b), —NR_(9a)C(O)OR_(9b),—OC(O)CR_(9a)R_(9b)R_(9c), —OC(S)CR_(9a)R_(9b)R_(9c), optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl,wherein R_(9a), R_(9b), and R_(9c) are each independently selected fromthe group consisting of hydrogen, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; R₂ is selected from thegroup consisting of hydrogen and optionally substituted C1-4 alkyl; R₃is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; R₄ is selected from thegroup consisting of hydrogen and optionally substituted C1-4 alkyl; R₅is selected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl; and R₆ is selected from thegroup consisting of hydrogen, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted alkyl, optionallysubstituted heteroalkyl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl; or a salt thereof.
 2. Themethod of claim 1, wherein said compound is represented by formula (I-e)or (II-e)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenyl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, whereinthe phenyl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, or 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C1-4 alkyl, C1-4alkoxy, halo, halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy,amino, —O(CH₂)₂NR_(10a)R_(10b), —S(O)₂NR_(10a)R_(10b),—OS(O)₂NR_(10a)R_(10b), and —NR_(10a)S(O)₂R_(10b), wherein R_(10a) andR_(10b) are each independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, and optionallysubstituted heterocycloalkyl; B is an optionally substituted ring systemselected from the group consisting of thiophen-2-yl, thiophen-3-yl,furan-3-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, imidazo[1,2-a]pyridin-3-yl,benzo[b]thiophen-3-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1H-imidazol-1-yl, pyrazin-2-yl, pyridazin-4-yl,1H-pyrrol-2-yl and thiazol-5-yl, wherein the thiophen-2-yl,thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl,1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-imidazol-1-yl,pyrazin-2-yl, pyridazin-4-yl, 1H-pyrrol-2-yl, or thiazol-5-yl isoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of cyano, hydroxy, C₁-4 alkyl, C2-4alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C1-4 alkoxy, halo,halo-substituted-C1-4 alkyl, halo-substituted-C1-4 alkoxy, amino,—C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C1-4 alkyl; and R₅ is selected from thegroup consisting of C1-10 alkyl, prop-1-en-2-yl, cyclohexyl,cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl,benzhydryl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, or1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C2-4 alkenyl, C2-4alkynyl, C3-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(11b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C1-4 alkyl; or a salt thereof.
 3. The methodof claim 1, wherein said compound is represented by formula (I-f),(II-f), (I-g), or (II-g)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl; q is an integer from0 to 4; each Z is independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C2-4alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C1-4 alkyl; and R₅ is selected from thegroup consisting of isopropyl, methyl, ethyl, prop-1-en-2-yl, isobutyl,cyclohexyl, sec-butyl, (S)-sec-butyl, (R)-sec-butyl,1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl,(R)-1-hydroxypropan-2-yl, and nonan-2-yl, or R₅ is selected from thegroup consisting of (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C2-4 alkenyl, C2-4alkynyl, C3-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(11b) are each independently selected from the groupconsisting of hydrogen and C1-4 alkyl; or a salt thereof.
 4. The methodof claim 1, wherein said compound is represented by-formula (I-h),(II-h), (I-i), (II-i), (I-j), (II-j), (I-k), or (II-k)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl; q is an integer from0 to 4; r is 0 or 1; W and V are each independently a substituentselected from the group consisting of C1-4 alkyl, halo,halo-substituted-C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b) wherein R_(11a) and R_(11b) areeach independently selected from the group consisting of hydrogen andC1-4 alkyl; and R₅ is selected from the group consisting of C1-10 alkyl,prop-1-en-2-yl, cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl,oxetan-2-yl, oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl,tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl,(4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl,wherein the C1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl,2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl,tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl, and1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethylis optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of hydroxy, C1-4 alkyl, andhalo-substituted-C1-4alkyl, or R₅ is selected from the group consistingof (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C₁-4 alkyl, C2-4 alkenyl, C2-4alkynyl, C3-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(11b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C₁₋₄ alkyl; or a salt thereof.
 5. The methodof claim 3, wherein said compound is represented by formula (II-f)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl; q is an integer from0 to 4; each Z is independently a substituent selected from the groupconsisting of C1-4 alkyl, halo, halo-substituted-C1-4 alkyl, C2-4alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C1-4 alkoxy, cyano, amino,C(O)R_(11a), —S(O)₀₋₂R_(11a), —C(O)OR_(11a), and —C(O)NR_(11a)R_(11b),wherein R_(11a) and R_(11b) are each independently selected from thegroup consisting of hydrogen and C1-4 alkyl; and R₅ is selected from thegroup consisting of isopropyl, methyl, ethyl, prop-1-en-2-yl, isobutyl,cyclohexyl, sec-butyl, (S)-sec-butyl, (R)-sec-butyl,1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl,(R)-1-hydroxypropan-2-yl, and nonan-2-yl, or R₅ is selected from thegroup consisting of (i), (ii), (iii), (iv), and (v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C2-4 alkenyl, C2-4alkynyl, C3-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(11b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C1-4 alkyl; or a salt thereof.
 6. The methodof claim 3, wherein said compound is represented by formula (II-g)

wherein A is an optionally substituted ring system selected from thegroup consisting of phenol-4-yl and 1H-indol-3-yl; Z is a substituentselected from the group consisting of C1-4 alkyl, halo,halo-substituted-C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6cycloalkyl, C1-4 alkoxy, cyano, amino, C(O)R_(11a), —S(O)₀₋₂R_(11a),—C(O)OR_(11a), and —C(O)NR_(11a)R_(11b), wherein R_(11a) and R_(11b) areeach independently selected from the group consisting of hydrogen andC1-4 alkyl; and R₅ is selected from the group consisting of isopropyl,methyl, ethyl, prop-1-en-2-yl, isobutyl, cyclohexyl, sec-butyl,(S)-sec-butyl, (R)-sec-butyl, 1-hydroxypropan-2-yl,(S)-1-hydroxypropan-2-yl, (R)-1-hydroxypropan-2-yl, and nonan-2-yl, orR₅ is selected from the group consisting of (i), (ii), (iii), (iv), and(v)

wherein n is an integer from 1 to 6, m is an integer from 0 to 6, p isan integer from 0 to 5, and each R is independently selected from thegroup consisting of cyano, hydroxy, C1-4 alkyl, C2-4 alkenyl, C2-4alkynyl, C3-6 cycloalkyl, C1-4 alkoxy, halo, halo-substituted-C1-4alkyl, halo-substituted-C1-4 alkoxy, amino, —C(O)R_(12a),—S(O)₀₋₂R_(12a), —C(O)OR_(12a), and —C(O)NR_(12a)R_(12b), and whereinR_(12a) and R_(12b) are each independently selected from the groupconsisting of hydrogen and C1-4 alkyl; or a salt thereof.
 7. The methodof claim 5, wherein A is phenol-4-yl.
 8. The method of claim 5, whereinA is 1H-indol-3-yl.
 9. The method of claim 5, wherein R₅ is selectedfrom the group consisting of isopropyl, methyl, ethyl, isobutyl,cyclohexyl, hydroxypropan-2-yl, sec-butyl, 3-ethoxy-1-methylpropyl,1-methoxy-4-pentyl, and 1-methoxy-3-butyl.
 10. The method of claim 5,wherein each Z is independently selected from the group consisting ofmethyl, ethynyl, cyclopropyl, fluoro, chloro, trifluoromethyl, andcyano.
 11. The method of claim 6, wherein R₅ is selected from the groupconsisting of isopropyl, methyl, ethyl, isobutyl, cyclohexyl,hydroxypropan-2-yl, sec-butyl, 3-ethoxy-1-methylpropyl,1-methoxy-4-pentyl, and 1-methoxy-3-butyl.
 12. The method of claim 6,wherein Z is selected from the group consisting of methyl, ethynyl,cyclopropyl, fluoro, chloro, trifluoromethyl, and cyano.
 13. The methodof claim 6, wherein A is 1H-indol-3-yl; R₅ is selected from the groupconsisting of isopropyl, methyl, ethyl, isobutyl, cyclohexyl,hydroxypropan-2-yl, sec-butyl, 3-ethoxy-1-methylpropyl,1-methoxy-4-pentyl, and 1-methoxy-3-butyl; and Z is selected from thegroup consisting of methyl, ethynyl, cyclopropyl, fluoro, chloro,trifluoromethyl, and cyano.
 14. The method of claim 1, wherein saidcompound is selected from the group consisting of

and salts thereof.
 15. The method of claim 5, wherein said compound is acompound selected from the group consisting of

and salts thereof.
 16. The method of claim 3, wherein said compound isselected from the group consisting of

and salts thereof.